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Landscape denudation in actively deforming mountain ranges is controlled by a combination of rock uplift and surface runoff induced by precipitation. Whereas the relative contribution of these factors is important to our understanding of the evolution of orogenic topography, no consensus currently exists concerning their respective infl uences. To address this question, denudation rates at centennial to millennial time scales were deduced from 10Be concentrations in detrital sediments derived from 30 small basins (10-600 km2) in an ~200-km-wide region in central Nepal. Along a northward, strike-perpendicular transect, average denudation rates sharply increase from

Whereas the existence of pronounced orbitally controlled periodicities is a major feature of Earth climate, its impact on landscape dynamics remains poorly understood. We use a Landscape Evolution Model (LEM) to systematically investigate the response of landscapes to a range of periodic oscillations in precipitation. The resulting sediment-flux evolution displays a pronounced sensitivity to the period of the input precipitation signal, such that, for a given erodibility, a specific periodicity maximizes the amplitude of the response. This optimal period of "resonance" scales as the inverse of the erodibility, but is progressively filtered out of the response when the intensity of hillslope diffusion increases. This frequency-dependent landscape behavior displayed by our model provides a mechanistic perspective on Molnar's (2004) proposition that ubiquitous changes in Late Cenozoic continental denudation could result directly from modifications in the spectral content of the climatic signal. © 2013. American Geophysical Union. All Rights Reserved.

Several processes contribute to denudation in high-mountain environments. Of these, glacial erosion is particularly difficult to constrain, despite its critical importance in the evolution of many mountain ranges. In this study, we present a new data set of 10Be concentrations in fluvial sediments sampled along the Marsyandi River and its main tributaries in central Nepal. We interpret the 10Be concentrations as being significantly impacted by glacially derived sediments along the Marsyandi River. Such additions complicate conventional interpretations of 10Be-derived catchment-scale denudation rates. Using a simple linear mass-conservation formulation, we invert our data set in order to separate the different denudational contributions to the observed signal, as well as to constrain their magnitude and spatial distribution. Our results suggest significant variations in glacial erosion, both in space and magnitude, within the Marsyandi catchment. © 2012. American Geophysical Union. All Rights Reserved.

The past decade has seen a rapid increase in the application of high-resolution imagery and geographic-based information systems across every segment of society from security intelligence to product marketing to scientific research. Google Earth has positioned itself at the forefront of this spatial information wave by providing free access to high-resolution imagery through a simple, user-friendly interface. Whereas Google Earth imagery has been widely exploited across the earth sciences for spatial visualization, education, and place-based searches, few studies have utilized the highresolution imagery to yield quantitative insights about the processes and mechanisms acting at the earth's surface. In this paper, we detail the benefits of the underlying high-resolution imagery available within Google Earth, review the limited published research to date, and utilize this imagery to quantitatively illuminate previously difficult and unresolved questions within the discipline of geomorphology involving: (1) channel-width variability and scaling relations in the tectonically active Himalaya; (2) landslide characteristics related to large magnitude climatic and tectonic events in Haiti; and (3) identification and quantification of laterally offset geomorphic features within eastern California. In each example, we compare analyses using freely available Google Earth imagery with standard imagery and techniques (e.g., Landsat, ASTER, lidar) to demonstrate the potential benefits of using high-spatial resolution Google Earth imagery over established methodologies. In addition, we discuss the potential limitations and problems with using the imagery currently available in Google Earth and propose favorable future applications, namely studies in remote terrains and those requiring high-resolution imagery across a large spatial extent, where purchasing such imagery in an academic environment would be costprohibitive. Whether as a supplement, for reconnaissance, or as the primary data set, high-resolution Google Earth imagery, when properly applied, holds great promise for quantitatively tackling previously unresolved problems in the study of earth surface processes. © 2012 The Geological Society of America. All rights reserved.

We present a mechanical analysis of the problem of slip partitioning between the major thrust systems in a collisional range. We focus on two structures in the Himalayas of central Nepal: the Main Himalayan Thrust (MHT) and the Main Central Thrust (MCT). We use finite element modeling to test the influence of various parameters, such as friction coefficients and surface processes, and we investigate how they affect the distribution of deformation between these two faults. We observe that reproduction of the late Quaternary kinematic pattern across the range with our model requires strict conditions on the friction coefficients, such that the MHT is very weak, whereas the MCT is significantly stronger. The most important parameter that controls slip partitioning appears to be the dip angle of the MCT, with a gentler or steeper MCT promoting or inhibiting slip, respectively. We also show that transient loading and unloading through focused glacial erosion in the higher part of the range can unclamp the MCT and allow a significant increase in slip rates. The results of this mechanical sensitivity investigation have important implications for the dynamics of the Himalayan wedge and point toward along-strike structural variations as a first-order control on slip partitioning. Copyright © 2011 by the American Geophysical Union.

[1] This article presents (U-Th)/He thermochronological data from the Longmen Shan belt, eastern Tibet. Located between the Songpan-Garze terrane and the Yangtze craton, this mountain range is one of the steepest margins of the Tibetan Plateau and an important area for the comprehension of the mechanisms that control the dynamics of such plateau borders in terms of spatial distribution of deformation or timing of topographic building. We describe several age-elevation transects and perform forward modeling of our data to derive quantitative information on the exhumation of the range. A major phase of exhumation started at 8-11 Ma, with an average rate of ~0.65 mm [a.sup.-1]. Comparison of zircon and apatite ages indicates that the eastern part of the range may have experienced a significant decrease in exhumation since 2-3 Ma. We use the distribution of finite exhumation across the major faults of the area to quantify their dip-slip throw rate over the last 10 Ma. The Beichuan Fault, which was activated during the 2008 Sichuan earthquake, is the major active structure of the Longmen Shah since the late Miocene, with an average thrusting slip rate between 0.4 and 1 mm [a.sup.-1]. Conversely, over the same time period, only minor dip-slip activity occurred on the Wenchuan Fault Zone. This distribution in space and time of exhumation and deformation is discussed and compared to the different proposed models for the geodynamical evolution of the eastern Tibetan margin. It also provides an important long-term perspective to put in context the destructive 2008 Sichuan earthquake that struck the central Longmen Shan. Citation: Godard, V., R. Pik, J. Lave, R. Cattin, B. Tibari, J. de Sigoyer, M. Pubellier, and J. Zhu (2009), Late Cenozoic evolution of the central Longmen Shah, eastern Tibet: Insight from (U-Th)/He thermochronometry, Tectonics, 28, TC5009, doi: 10.1029/2008TC002407.

Background: The use of dose administration aids in automated ward dispensing devices requires the repackaging of medications, which may impact their stability compared with the original manufacturer's packaging., Objectives: This study aimed to assess the physical and chemical stability of clozapine tablets for up to 84 days after repackaging., Methods: A total of 900 tablets of clozapine 100 mg (Viatris) were repackaged and stored under five different conditions to conduct physical and chemical stability tests on days 0, 28, 56 and 84. The results were compared with control tablets in their original packaging. Visual inspections of tablet appearance were performed. Physical tests included assessments of mass uniformity, friability and resistance to crushing, following the standards of the European Pharmacopoeia 11th edition. The chemical stability was determined using ultra-high performance liquid chromatography with tandem-mass spectrometry detection (UHPLC-MS/MS) to measure clozapine concentration, N-desmethyl-clozapine, and monitor clozapine degradation to detect formation of any degradation products other than N-desmethyl-clozapine., Results: Visual examination showed changes in the appearance of tablets only in those stored under UV light. Mass uniformity met standards for all tablets over 84 days. None passed the friability test due to tablet cracking after tumbling. A gradual deterioration in tablet hardness was observed with the resistance to crushing test. In terms of chemical stability, N-desmethyl-clozapine was undetected in any of the tablets stored under all conditions, and the mean concentration of clozapine remained within the target range over 84 days., Conclusion: N-desmethyl-clozapine was not detected and clozapine concentrations remained stable under all storage conditions. The tablets were compliant with the mass uniformity test in each condition. However, the tablets were cracked in the friability test and gradual deterioration in tablet hardness was observed. In the light of these results, the Vinatier Hospital pharmacy has chosen to establish a shelf life for clozapine tablets of 84 days., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Physical restraint (PR) is prescribed in patients receiving invasive mechanical ventilation in the intensive care unit (ICU) to avoid unplanned removal of medical devices. However, it is associated with an increased risk of delirium. We hypothesise that a restrictive use of PR, as compared with a systematic use, could reduce the duration of delirium in ICU patients receiving invasive mechanical ventilation., Methods and Analysis: The Restrictive use of Restraints and Delirium Duration in ICU (R2D2-ICU) study is a national multicentric, parallel-group, randomised (1:1) open-label, controlled, superiority trial, which will be conducted in 10 ICUs. A total of 422 adult patients requiring invasive mechanical ventilation for an expected duration of at least 48 hours and eligible for prescription of PR will be randomly allocated within 6 hours from intubation to either the restrictive PR use group or the systematic PR use group, until day 14, ICU discharge or death, whichever comes first. In both groups, PR will consist of the use of wrist straps. The primary endpoint will be delirium or coma-free days, defined as the number of days spent alive in the ICU without coma or delirium within the first 14 days after randomisation. Delirium will be assessed using the Confusion Assessment Method-ICU twice daily. Key secondary endpoints will encompass agitation episodes, opioid, propofol, benzodiazepine and antipsychotic drug exposure during the 14-day intervention period, along with a core outcome set of measures evaluated 90 days postrandomisation., Ethics and Dissemination: The R2D2-ICU study has been approved by the Comité de Protection des Personnes (CPP) ILE DE FRANCE III-PARIS (CPP19.09.06.37521) on June 10th, 2019). Participant recruitment started on 25 January 2021. Results will be published in international peer-reviewed medical journals and presented at conferences., Trial Registration Number: NCT04273360., Competing Interests: Competing interests: RS received grants from the French Ministry of Health and from LB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Delirium is a severe complication that is associated with short-term adverse events, prolonged hospital stay and neurological sequelae in survivors. Automated pupillometry is an easy-to-use device that allows for accurate objective assessment of the pupillary light responses in comatose patients in the intensive care unit (ICU). Whether automated pupillometry might predict delirium in critically ill patients is not known. We hypothesise that automated pupillometry could predict the occurrence of delirium in critically ill patients without primary brain injury, requiring more than 48 hours of invasive mechanical ventilation in the ICU., Methods and Analysis: The PupillOmetry for preDIction of DeliriUM in ICU (PODIUM) study is a prospective cohort study, which will be conducted in eight French ICUs in the Paris area. We aim to recruit 213 adult patients requiring invasive mechanical ventilation for more than 48 hours. Automated pupillometry (Neurological Pupil Index; NPi-200, Neuroptics) will be assessed two times per day for 7 days. Delirium will be assessed using the Confusion Assessment Method in ICU two times per day over 14 days in non-comatose patients (Richmond Agitation and Sedation Scale ≥-3).The predictive performances of the seven automated pupillometry parameters (ie, pupillary diameter, variation of the pupillary diameter, pupillary constriction speed, pupillary dilatation speed, photomotor reflex latency, NPi and symmetry of pupillary responses) measured to detect the delirium occurrence within 14 days will be the main outcomes. Secondary outcomes will be the predictive performances of the seven automated pupillometry parameters to detect complications related to delirium, ICU length of stay, mortality, functional and cognitive outcomes at 90 days., Ethics and Dissemination: The PODIUM study has been approved by an independent ethics committee, the Comité de Protection des Personnes (CPP) OUEST IV-NANTES (CPP21.02.15.45239 32/21_3) on 06 April 2021). Participant recruitment started on 15 April 2022. Results will be published in international peer-reviewed medical journals and presented at conferences., Trial Registration Number: NCT05248035; clinicaltrials.gov., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

It has long been hypothesized that climate can modify both the pattern and magnitude of erosion in mountainous landscapes, thereby controlling morphology, rates of deformation, and potentially modulating global carbon and nutrient cycles through weathering feedbacks. Although conceptually appealing, geologic evidence for a direct climatic control on erosion has remained ambiguous owing to a lack of high-resolution, long-term terrestrial records and suitable field sites. Here we provide direct terrestrial field evidence for long-term synchrony between erosion rates and Milankovitch-driven, 400-kyr eccentricity cycles using a Plio-Pleistocene cosmogenic radionuclide paleo-erosion rate record from the southern Central Andes. The observed climate-erosion coupling across multiple orbital cycles, when combined with results from the intermediate complexity climate model CLIMBER-2, are consistent with the hypothesis that relatively modest fluctuations in precipitation can cause synchronous and nonlinear responses in erosion rates as landscapes adjust to ever-evolving hydrologic boundary conditions imposed by oscillating climate regimes., (© 2023. The Author(s).)

Mass-participation events in temperate forests are now well-established features of outdoor activities and represent high-risk activities regarding human exposition to tick bites. In this study we used a citizen science approach to quantify the space-time frequency of tick bites and undetected tick bites among orienteers that participated in a 6-day orienteering competition that took place in July 2018 in the forests of Eastern France, and we looked at the use and efficacy of different preventive behaviors. Our study confirms that orienteers are a high-risk population for tick bites, with 62.4% of orienteers bitten at least once during the competition, and 2.4 to 12.1 orienteers per 100 orienteers were bitten by ticks when walking 1 km. In addition, 16.7% of orienteers bitten by ticks had engorged ticks, meaning that they did not detect and remove their ticks immediately after the run. Further, only 8.5% of orienteers systematically used a repellent, and the use of repellent only partially reduced the probability of being bitten by ticks. These results represent the first attempt to quantify the risk of not immediately detecting a tick bite and provide rare quantitative data on the frequency of tick bites for orienteers according to walking distance and time spent in the forest. The results also provide information on the use of repellent, which will be very helpful for modeling risk assessment. The study also shows that prevention should be increased for orienteers in France.

Lyme borreliosis is the most common tick-borne disease in the northern hemisphere. In Europe, it is transmitted by Ixodes ticks that carry bacteria belonging to the Borrelia burgdorferi sensu lato complex. The objective of this work was to explore eco-epidemiological factors of Lyme borreliosis in peri-urban forests of France (Sénart, Notre-Dame and Rambouillet). We investigated whether the introduction of Tamias sibiricus in Sénart could alter the density of infected ticks. Moreover, the density and tick infection were investigated according to the tree species found in various patches of Sénart forest. For this purpose, ticks were sampled during 3 years. In the Sénart forest, the density of nymph and adult ticks showed no significant difference between 2008, 2009 and 2011. The nymph density varied significantly as a function of the month of collection. Regarding the nymphs, a higher rate of infection and infected density were found in 2009. Plots with chipmunks (C) presented a lower density of both nymphs and adult ticks than plots without chipmunks (NC) did. A higher rate of infection of nymphs with Borrelia was seen in C plots. The prevalence of the various species of Borrelia was also found to vary between C and NC plots with the year of the collect. The presence of chestnut trees positively influenced the density of both nymphs and adults. The infected nymph density showed a significant difference depending on the peri-urban forest studied, Sénart being higher than Rambouillet. The prevalence of Borrelia species also differed between the various forests studied. Concerning the putative role that Tamias sibiricus may play in the transmission of Borrelia, our results suggest that its presence is correlated with a higher rate of infection of questing ticks by Borrelia genospecies and if its population increases, it could play a significant role in the risk of transmission of Lyme borreliosis.

Background: Although introduced nearly 40 years ago, Geographic Information Systems (GISs) have never been used to study Occupational Health information regarding the different types, scale or sources of data. The geographic distribution of occupational diseases and underlying work activities were always analyzed independently. Our aim was to consider the French Network of Occupational Disease (OD) clinics, namely the "French National OD Surveillance and Prevention Network" (rnv3p) as a spatial object in order to describe its catchment., Methods: We mapped rnv3p observations at the workplace level. We initially analyzed rnv3p capture with reference to its own data, then to the underlying workforce (INSEE "Employment Areas"), and finally compared its capture of one emblematic occupational disease (mesothelioma) to an external dataset provided by a surveillance system thought to be exhaustive (PNSM)., Results: While the whole country is covered by the network, the density of observations decreases with increase in the distance from the 31 OD clinics (located within the main French cities). Taking into account the underlying workforce, we show that the probability to capture and investigation of OD (assessed by rates of OD per 10,000 workers) also presents large discrepancies between OD clinics. This capture rate might also show differences according to the disease, as exemplified by mesothelioma., Conclusion: The geographic approach to this network, enhanced by the possibilities provided by the GIS tool, allow a better understanding of the coverage of this network at a national level, as well as the visualization of capture rates for all OD clinics. Highlighting geographic and thematic shading zones bring new perspectives to the analysis of occupational health data, and should improve occupational health vigilance and surveillance.

Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.

Background: The long-term risk of chronic kidney disease (CKD) in lithium (Li)-treated patients has been well established in the recent years., Methods: We have evaluated GFR and serum calcium monitoring in 1179 Li-treated outpatients from an ambulatory laboratory database study. This has been performed in a single private laboratory in Paris from February 1997 to December 2004. Estimated GFR (eGFR) has been calculated using the abbreviated MDRD equation., Results: During an 8-year period, 695 patients (59%) had at least one serum creatinine measurement, whereas 484 had no creatinine measurement. The former group had also more frequent serum Li measurements. Mean serum lithium levels, were similar in both groups, 0.65 mmol/l vs 0.62 mmol/l. The percentage of patients with CKD stage 3 (eGFR 30-59 ml/min/1.73 m(2)) were 36%, 53%, 73% and 77%, and with CKD stage 4, 3%, 5%, 5%, 8% in patients aged 20-39, 40-59, 60-69, and > or = 70 years respectively. There was no significant rise in creatinine measurements (from 35% of the patients with at least one serum creatinine in 2003 to 39% in 2004; P = 0.66) despite intervention to intensify GFR monitoring by physicians. Serum calcium was tested at least once in 212 patients (18%) of whom 15 (7%) were found with hypercalcaemia., Conclusion: A very high percentage of Li-treated outpatients have low eGFR. GFR monitoring is neglected in these patients, the majority of whom are no longer attending specialized clinics. Hypercalcaemia is less common but serum calcium monitoring is even more neglected. Ambulatory laboratory database surveillance provides a powerful means to contribute to CKD screening and monitoring.

Background: The Muir-Torre syndrome is an autosomal dominant hereditary condition predisposing to cancer. It is characterized by skin tumors associated with adenocarcinoma of the colon or other neoplasias observed in the context of hereditary non-polyposis colorectal cancer (HNPCC). The Muir-Torre syndrome is also characterized by the frequent presence of multiple colonic polyps and the relatively moderate aggressivity of the tumors., Case Report: We studied a family with Muir-Torre syndrome. We sequenced the exons of the hMSH2 gene in this family and identified heterozygous germinal mutation by G insert at position 2427 (2427insG). This mutation changes the lecture phase producing a premature codon stop., Discussion: Our study confirms the predominant responsibility of the hMSH2 gene in Tuir-Torre syndrome. This clinical case and data reported in the literature demonstrate the importance of searching for a history of non-polyposis colorectal cancer in patients and relatives and the unstable genome characteristic of these tumors found in sebaceous tumors or keratoacanthomas. Sequencing the hMSH2 gene should be a priority when clinical features, history and laboratory tests suggest Muir-Torre syndrome.

The molecular diagnosis of genetic abnormalities responsible for genetic predisposition to breast cancer is made difficult by the large size of the genes and the diversity of gene mutations found within these genes. The molecular diagnosis of responsible mutations requires the implementation of particular analytical methods, for which we give two examples, the protein truncation test and the direct sequence analysis of the cDNA. Results obtained with these two methods demonstrate the interest of studying the sequence of messenger RNA expressed by predisposing genes. The study also describes an abnormal splicing and two rearrangements responsible for genetic predisposition to breast cancer.

A chronic administration of three ganciclovir gels (0.2%, 0.05%, 0.0125%) was compared with a placebo gel and a 3% acyclovir ophthalmic ointment in the treatment of HSV-1 rabbit keratitis. All the ganciclovir gels showed a clinical efficacy: a significant reduction of the corneal ulcer area, clouding and vascularization (p < 0.05) and a fast inhibition of HSV isolates into tear film with the 0.2% and 0.05% ganciclovir gels. However the efficacy was slower than using acyclovir ointment. No significant difference could be shown between the 0.2% and 0.05% ganciclovir gels or the 0.05% ganciclovir gel and the acyclovir treatment on viral isolation, when it was performed on pooled samples. The distribution of ganciclovir and acyclovir into the rabbit eyes (HPLC methods), were similar but markedly higher in solid tissues than ocular fluids. It might explain the recovery from tissue damages. The mean corneal ganciclovir concentrations were largely higher than ED 50 of ganciclovir for HSV-1. No toxicity was expected, due to very limited systemic availability. This study suggests a comparable activity on HSV-1 superficial keratitis between 0.05%, 0.2% ganciclovir gels and 3% acyclovir ointment. Higher concentration of ganciclovir gels are probably necessary in order to treat the HSV-1 kerato-uveitis.

The acquisition of drug resistance in vivo was investigated by 7 serial passages (from P0 to P7) of herpes simplex virus (HSV-1) in rabbit cornea treated with either IUdR (idoxuridine), IDC (idoxycytidine), ACV (acyclovir), TFT (trifluridine), or Ara A (adenine arabinoside). Therapeutic failure was acquired gradually: at P3 for IUdR, at P4 for ACV and at P5 for TFT. At P7, viral thymidine kinase (TK) activity was reduced to 5.6% of the parental strain for IUdR, to 7.5% for ACV and to 4.6% for TFT treatment. No signs of clinical unresponsiveness occurred with IDC or Ara A. The in vitro determination of antiviral drug sensitivity performed by the dye-uptake assay on HSV isolates at each passage showed a correlation between the increase in the 50% effective dose (ED50) and the increase of ulcer area grade at each passage under antiviral drug (p less than 0.1). Both IUdR- and TFT-resistant HSV1 developed cross-resistances to TK dependent drugs. However ACV-resistant HSV1 did not show cross-resistance to other antiviral TK dependent drugs. The acquisition of the cross-resistances is discussed, and the practical implications in case of therapeutic failures are suggested.

Fasting and postprandial (or post-glucose load) plasma glucose, total HbA1 and fructosamine (F) were simultaneously assessed in 371 diabetic patients (125 insulin dependent and 246 non-insulin dependent) and in 122 nondiabetic subjects, (98 with normal glucose tolerance and 24 with impaired glucose tolerance). Fructosamine yielded nearly similar information as HbA1 about glycemic control, since similar relationships were observed between plasma glucose values and HbA1 or fructosamine levels in the different groups. A longitudinal study performed during a three-month follow-up in 74 diabetic patients and extended to six months in 19 of them, without any modification of treatment, indicated that reproducibility of HbA1 and fructosamine was nearly the same with a slight advantage for HbA1. The only clinically significant difference results from the longer half-life of hemoglobin when compared to serum proteins. Fructosamine assay should be proposed as a complement of HbA1 in the management of diabetic patients when detection of recent metabolic changes is needed.