Usefulness of circulating tumor DNA from cerebrospinal fluid in recurrent high-grade glioma.

Molecular documentation at relapse of high-grade glioma is an urgent need for patient care. A prospective pilot study was conducted to assess the rate of mutation detection using targeted deep sequencing on circulating tumor DNA from cerebrospinal fluid (CSF) after chemo-radiotherapy based treatment. Fifteen patients were included: 13 patients with glioblastoma, 1 patient with gliosarcoma and 1 patient with anaplastic astrocytoma. At progression, 10/15 patients (67%) had detectable mutations in the CSF. Among them, 5/10 patients harbored at least one common mutation between initial tumor and ctDNA. CSF protein level and cfDNA concentration were higher, although not significant, in the ctDNA positive group versus ctDNA negative group (1.17g/L vs. 0.79g/L). Molecular documentation obtained from ctDNA in CSF at the time of relapse is informative in around two-thirds of the patients.

Time-frequency analysis of two-photon absorption effect during optical rectification in a ZnTe crystal pumped at 1.024 µm.

Optical rectification in nonlinear crystals is a well-established method for generating terahertz (THz) waves from ultra-short optical pulses. To achieve high conversion efficiency, the phase-matching conditions between the pump pulse and the generated THz wave within the nonlinear medium must be satisfied. For a ytterbium laser operating at 1.024 µm, a severe phase mismatch occurs in the zinc telluride (ZnTe) crystal, preventing the efficient generation of broadband THz pulses. Using time-frequency analysis, we show that the ultrafast charge carrier dynamic, mainly induced by two-photon absorption, generated in the nonlinear medium during optical rectification processes in ZnTe, plays a crucial role in the filtering of the out-of-phase components of the THz signal, thus enabling the recovery of broadband THz pulse generations.

SCREENER, an educational game for teaching the Drug Discovery and Development process.

Although the use of games as an educational strategy is an important current trend, there is practically no option available for training people on the Drug Discovery and Development (DDD) process. To fill this gap, we designed "SCREENER", a science game that is intended to be educational, but also challenging and interesting enough to ensure player engagement. Our main target audience is students of postgraduate programs in pharmacology, medicinal chemistry, pharmacy, and medicine. This game could also be of interest to the pharmaceutical industry and regulatory and patent agencies for training new employees. We discuss the creation of SCREENER, a hybrid of board and card games, and present its components with some examples of cards and resources, as well as the dynamics of the game. SCREENER mimics the process of drug discovery and development from validating a target to registering the new drug with the regulatory agency, and can be played individually (self-learning) or with the help of a monitor who assists up to six players/teams. Briefly, 29 task cards categorized in four major areas (efficacy, safety, pharmacokinetics, and pharmaceutical development) must be purchased sequentially. Classic characteristics of games such as decision making and challenge have been incorporated. More in-depth information on the tasks and technical terms is available through QR codes. The vagaries of the DDD process are mimicked by the bonus/setback cards. The evaluation of our first test with students is presented and supports the usefulness of this new tool.

SCREENER, an educational game for teaching the Drug Discovery and Development process

Although the use of games as an educational strategy is an important current trend, there is practically no option available for training people on the Drug Discovery and Development (DDD) process. To fill this gap, we designed "SCREENER", a science game that is intended to be educational, but also challenging and interesting enough to ensure player engagement. Our main target audience is students of postgraduate programs in pharmacology, medicinal chemistry, pharmacy, and medicine. This game could also be of interest to the pharmaceutical industry and regulatory and patent agencies for training new employees. We discuss the creation of SCREENER, a hybrid of board and card games, and present its components with some examples of cards and resources, as well as the dynamics of the game. SCREENER mimics the process of drug discovery and development from validating a target to registering the new drug with the regulatory agency, and can be played individually (self-learning) or with the help of a monitor who assists up to six players/teams. Briefly, 29 task cards categorized in four major areas (efficacy, safety, pharmacokinetics, and pharmaceutical development) must be purchased sequentially. Classic characteristics of games such as decision making and challenge have been incorporated. More in-depth information on the tasks and technical terms is available through QR codes. The vagaries of the DDD process are mimicked by the bonus/setback cards. The evaluation of our first test with students is presented and supports the usefulness of this new tool.

Active terahertz time differentiator using piezoelectric micromachined ultrasonic transducer array.

The rapid growth of information technology is closely linked to our ability to modulate and demodulate a signal, whether in the frequency or in the time domain. Recent demonstrations of terahertz (THz) modulation involve active semiconductor metamaterial surfaces or use of a grating-based micromirror for frequency offset tuning. However, a wideband and active differentiator in the THz frequency band is yet to be demonstrated. Here, we propose a simple method to differentiate a THz pulse by inducing tiny phase changes on the THz beam path using a piezoelectric micromachined ultrasonic transducer array. We precisely demonstrate that the modulated THz signal detected after the piezoelectric device is proportional to the first-order derivative of the THz pulse. The proposed technique will be able to support a wide range of THz applications, such as peak detection schemes for telecommunication systems.

Transfer of orbital angular momentum of light to plasmonic excitations in metamaterials.

The emergence of the vortex beam with orbital angular momentum (OAM) has provided intriguing possibilities to induce optical transitions beyond the framework of the electric dipole interaction. The uniqueness stems from the OAM transfer from light to material, as demonstrated in electronic transitions in atomic systems. In this study, we report on the OAM transfer to electrons in solid-state systems, which has been elusive to date. Using metamaterials (periodically textured metallic disks), we show that multipolar modes of the surface electromagnetic excitations (so-called spoof localized surface plasmons) are selectively induced by the terahertz vortex beam. Our results reveal selection rules governed by the conservation of the total angular momentum, which is confirmed by numerical simulations. The efficient transfer of light's OAM to elementary excitations in solid-state systems at room temperature opens up new possibilities of OAM manipulation.

N-Difluoromethyl-triazole as a constrained scaffold in peptidomimetics.

The N-difluoromethyl triazolo-ß-aza-ε-amino acid present in the core of peptides led to constrained conformations due to CH-F and NH-F interactions. Pseudotetrapeptides were obtained in excellent yields directly by click chemistry between azidodifluoroacetamides and alkynes, both linked to an amino acid. This work demonstrates that the N-difluoromethyltriazole scaffold can induce extended structures to ß-strand mimics.

PIFA-mediated ethoxyiodination of enamides with potassium iodide.

The regioselective ethoxyiodination of enamides was developed using PIFA in combination with potassium iodide in ethanol. The reaction proceeds regioselectively with excellent yields and diastereoselectivities, providing valuable synthons for further functionalisations. Control experiments were conducted, indicating that the transformation occurs through an ionic manifold involving an in situ generated hypoiodite species.

Neodymium uranyl peroxide synthesis by ion exchange on ammonium uranyl peroxide nanoclusters.

This study demonstrates the ability of ammonium uranyl peroxide nanoclusters U32R-NH4 to undergo exchange in between NH4(+) and trivalent (Nd(3+)) or tetravalent (Th(4+)) cations in the solid state. It paves the way for new promising routes for the synthesis of mixed uranyl peroxides. The exchange ability may also be considered for solution decontamination and synthesis of new mixed actinide-oxide precursors. Both of these applications could be used in the nuclear industry.

Distinct expression of interleukin (IL)-36α, ß and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease.

Interleukin (IL)-36α, IL-36ß and IL-36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL-36Ra or IL-38, another potential IL-36 inhibitor, limit uncontrolled inflammation. The expression and role of IL-36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36ß and IL-38 mRNA, was induced and correlated with IL-1ß and T helper type 17 (Th17) cytokines (IL-17A, IL-22, IL-23, CCL20). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, ß, γ, IL-36Ra and IL-38 were all elevated and correlated with IL-1ß, CCL3, CCL4 and macrophage colony-stimulating factor (M-CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at relatively low levels and correlated with IL-1ß and IL-17A. We suggest that only a minor subgroup of patients with RA (17-29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL-36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68⁺ macrophages, dendritic/Langerhans cells and CD79α⁺ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL-36ß and IL-36Ra were produced constitutively, but IL-36α, γ and IL-38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL-36 agonists/antagonists ratio.

Predictors of Long-Term Mortality in Oldest Old Patients (90+) Hospitalized to Medical Wards via the Emergency Department: The SAFES Cohort.

OBJECTIVES: To identify risk factors for long-term mortality in patients aged 90 years and over who are admitted to hospital through the emergency department. DESIGN: Prospective cohort study (SAFES cohort; Sujet Agé Fragile - Évaluation Suivi). SETTING: 8 university teaching hospitals and one regional, non-academic hospital in France. PARTICIPANTS: Among 1306 patients in the SAFES cohort, 291 patients aged 90 or over were included. MEASUREMENTS: At inclusion, we recorded socio-demographic data (age, sex, level of education, living alone or in an institution, number of children, presence of helper/caregiver), and data from geriatric evaluation (dependence status, risk of depression, dementia, delirium, nutritional status, walking disorders, risk of falls, comorbidities, risk of pressure sores). Vital status at 36 months was obtained from the treating physician, the general practitioner, administrative registers, or during follow-up consultations. RESULTS: Among 291 patients included, 190 (65.3%) had died at 36 months. Risk factors for mortality at 36 months identified by multivariate analysis were risk of malnutrition (HR 1.6, 95%CI 1.1-2.3, p=0.004) and delirium (HR 1.6, 95%CI 1.1-2.3, p=0.01). CONCLUSION: Risk of malnutrition and presence of delirium are risk factors for mortality at 36 months in subjects aged 90 years and over hospitalized through the emergency department.

Effect of extreme pump pulse reshaping on intense terahertz emission in lithium niobate at multimilliJoule pump energies.

We report on terahertz (THz) generation via optical rectification in a room-temperature lithium niobate crystal under variable pump pulse durations, ranging from 100 to 300 fs, at 800 nm center wavelength. The efficiency for the process is predicted to have an order of magnitude increase when longer duration Fourier-limited pump pulses are used. Our results confirm this increase in efficiency, and we report a record 800 nm pump energy conversion efficiency of 0.35% with a saturation at >240 fs pulse duration. While promising, our findings show a series of key problems that must be overcome before the theoretical limit can be achieved, including the influence of the pump bandwidth broadening due to the cascaded nonlinearity taking place within the crystal.

[Prognostic value of toxicities induced by targeted therapies in patients treated for a metastatic renal cell carcinoma]. / Valeur pronostique de la toxicité induite par les thérapies ciblées dans le carcinome rénal métastatique.

OBJECTIVE: To assess the prognostic value of clinical and biological variables in the era of targeted therapies, especially induced toxicity in patients treated for metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: A retrospective single-center study was performed in patients treated in our center from 2006 to 2012. The clinical and biological variables and toxicity data were retrospectively collected. Survival rates were calculated using the Kaplan-Meier method and compared by the Log-Rank test. Multivariate analysis was also performed using the Cox model. RESULTS: One hundred and two patients were included, with a median follow-up of 20 months. The median overall survival (OS) was 21 months, and 6 months for the progression free survival (PFS). As expected, the variables included in the Mozter prognostic score had a significant impact on OS (P < 0.0001) and PFS (P < 0.0001). However, hypoalbuminemia (P < 0.0001), brain metastasis (P = 0.003) and the absence of nephrectomy (P < 0.0001) were found as poor prognosis factors for OS. In addition, severe toxicity (grade 3-4) was significantly associated with higher OS (P < 0.0001) and PFS (P = 0.0003) and appeared as an independent factor in multivariate analysis for OS (P = 0.02) and PFS (P = 0.01). CONCLUSION: Severe toxicity induced by targeted therapies was found as a prognostic factor increasing significantly the survival. Further studies are needed to assess the real value of this factor in the development of sequential therapies for the treatment of RCC.

Terahertz phase contrast imaging of sorption kinetics in porous coordination polymer nanocrystals using differential optical resonator.

The enhancement of light-matter coupling when light is confined to wavelength scale volumes is useful both for studying small sample volumes and increasing the overall sensing ability. At these length scales, nonradiative interactions are of key interest to which near-field optical techniques may reveal new phenomena facilitating next-generation material functionalities and applications. Efforts to develop novel chemical or biological sensors using metamaterials have yielded innovative ideas in the optical and terahertz frequency range whereby the spatially integrated response over a resonator structure is monitored via the re-radiated or leaked light. But although terahertz waves generally exhibit distinctive response in chemical molecules or biological tissue, there is little absorption for subwavelength size sample and therefore poor image contrast. Here, we introduce a method that spatially resolves the differential near-field phase response of the entire resonator as a spectral fingerprint. By simultaneously probing two metallic ring resonators, where one loaded with the sample of interest, the differential phase response is able to resolve the presence of guest molecules (e.g. methanol) as they are adsorbed or released within the pores of a prototypical porous coordination polymer.

Is obesity a marker of robustness in vulnerable hospitalized aged populations? Prospective, multicenter cohort study of 1 306 acutely ill patients.

BACKGROUND: The "obesity paradox" is poorly understood in vulnerable older hospitalized populations. OBJECTIVES: To prospectively analyze the impact of body mass index (BMI) and comorbidities on early (6-week), one- and two-year mortality. DESIGN: Prospective multicenter study with a two-year follow-up of old patients participating in the SAFES cohort study. SETTINGS: Nine university hospitals in France. PARTICIPANTS: Patients aged 75 or older hospitalized in medical divisions through the emergency department. MEASUREMENT: Inpatients' characteristics were obtained through a comprehensive geriatric assessment of inpatients, conducted in the first week of hospitalization. All-cause mortalities at 6-week, one- and two-year were determined using bivariable and multivariable Cox proportional hazard model. RESULTS: The SAFES cohort included 1,306 patients, aged 85±6 years, with a majority of women (65%). One- and two-year mortality were inversely associated with BMI ≥30 kg/m2 while early mortality was not, and positively associated with age, burden of comorbidities, walking disorders, level of dependency and presence of a dementia syndrome. Survival rates between patients in low (< 18.0 kg/m2) and intermediate (18-24.9 and 25-29.9 kg/m2) BMI categories were not significant. CONCLUSION: While our findings seem to confirm the reality of the "obesity paradox" in vulnerable older hospitalized population, the exact understanding of underlying mechanisms and even the truthfulness of this paradoxical relationship are still fraught with considerable methodological, epidemiological and metabolic challenges.

Relationship between anticholinergic drug use and one-year outcome among elderly people hospitalised in medical wards via emergency department: the SAFES cohort study.

AIM: To investigate the relationship between anticholinergic drug use and one-year outcome of elderly patients hospitalised via the emergency department. METHODS: Prospective, multicentre, cohort study of patients aged 75 years and older. Comprehensive geriatric evaluation was performed. We included in this analysis all patients for whom data on drug use was available. Anticholinergic drugs were coded using the online database "Thesorimed". One-year mortality and nursing home admission were analysed using a Cox model, with matching on the propensity to use anticholinergic drugs. RESULTS: In total, 1176 subjects were included in this analysis, average age 85±6 years, 65% women. Overall, 144 (12%) were taking at least one anticholinergic drug. Mortality and nursing home admission at one year were respectively 29% and 30% in the anticholinergic group, and 34% and 33% respectively in subjects not taking anticholinergic drugs. No significant relationship was observed between anticholinergic drug use and the main endpoints. CONCLUSION: Although we did not observed any statistically significant relationship between use of anticholinergic drugs and one-year outcome in elderly patients, the long-term use of anticholinergic drugs can have deleterious effects on memory and functional capacity, and therefore requires prescriptions to be reviewed regularly.

Terahertz spectroscopy of the reactive and radiative near-field zones of split ring resonator.

A terahertz microscope has been used to excite and observe the resonant modes of a single split ring resonator in the reactive and radiative near-field zones. The two lowest resonant modes of an isolated split ring resonator with their corresponding radiation patterns are reported; they showed good agreement to simulations. The passage from the reactive to radiative near-field zone is also discussed. Further, our result introduced a novel technique to perform terahertz time-domain spectroscopy of samples a few tens of micrometers in size by measuring the in-plane radiative near-field zone.

Six-month outcome of elderly people hospitalized via the emergency department: the SAFES cohort.

BACKGROUND: The objective of the study was to identify factors predictive of 6-month institutionalization or mortality in frail elderly patients after acute hospitalization. METHODS: A prospective cohort of elderly subjects 75 years and older was set up in nine French teaching hospitals. Data obtained from a comprehensive geriatric assessment were used in a Cox model to predict 6-month institutionalization or mortality. Institutionalization was defined as incident admission either to a nursing home or other long-term care facility during the follow-up period. RESULTS: Crude institutionalization and death rates after 6 months of follow-up were 18% and 24%, respectively. Independent predictors of institutionalization were: living alone (HR=1.83; 95% CI=1.27-2.62) or a higher number of children (HR=0.86; 95% CI=0.78-0.96), balance problems (HR=1.72; 95% CI=1.19-2.47), malnutrition or risk thereof (HR=1.93; 95% CI=1.24-3.01), and dementia syndrome (HR=1.88; 95% CI=1.32-2.67). Factors found to be independently related to 6-month mortality were exclusively medical factors: malnutrition or risk thereof (HR=1.92; 95% CI=1.17-3.16), delirium (HR=1.80; 95% CI=1.24-2.62), and a high level of comorbidity (HR=1.62; 95% CI=1.09-2.40). Institutionalization (HR=1.92; 95% CI=1.37-2.71) and unplanned readmission (HR=4.47; 95% CI=3.16-2.71) within the follow-up period were also found as independent predictors. CONCLUSION: The main factors predictive of 6-month outcome identified in this study are modifiable by global and multidisciplinary interventions. Their early identification and management would make it possible to modify frail elderly subjects' prognosis favorably.

[Functional manifestations associated to corticosteroid therapy among the elderly]. / Manifestations fonctionnelles associées à la prise de corticoïdes chez les sujets âgés.

PURPOSE: Corticosteroid therapy is frequently prescribed in the elderly with potentially significant consequences in this frail population. The objective of this study was to describe the functional manifestations associated and the preventive measures prescribed with corticosteroid therapy among patients over 75 years old. PATIENTS AND METHODS: We conducted an exposed/non-exposed, prospective, multi-centre, observational study. Each exposed patient was sex and age (± 2 years) matched to two unexposed subjects. The sample included patients aged over 75 years treated with long-term corticosteroid therapy and hospitalized in an acute geriatric unit between June 2006 and November 2009. Sociodemographic and geriatric characteristics, history of corticosteroid therapy, clinical manifestations and preventive measures prescribed were collected. RESULTS: Fifty exposed and 100 unexposed patients were included. Mean age was 85±6 years. Prevalence of falls, osteoarticular complications, amyotrophy, vertebral fractures, lipodystrophy, purpura, hematomas and cataracts, and the number of medications were higher among patients taking corticosteroid therapy than in controls. Preventive measures were more often prescribed to patients under taking corticosteroid therapy (calcium and vitamin supplementation, potassium supplementation, anti-osteoporosis medication and gastroprotective agents). CONCLUSION: Functional manifestations associated with corticosteroid therapy are frequent among the elderly and may have serious consequences in this frail population. Attention should be paid to the prescription of preventive measures through comprehensive care.

First steps in adaptation of an evidential network for data fusion in the framework of medical remote monitoring.

This paper presents a medical remote monitoring application which aims at detecting falls. The detection system is based on three modalities: a wearable sensor, infrared sensors and a sound analysis module. The sound analysis is presented briefly. The multimodal fusion is made using the Dempster Schaffer theory through Evidential Network. A first evaluation of the use of data mining techniques in order to extract blindly data representatives is proposed. These representatives are used to continuously increase the system performances. The system is evaluated on a local recorded data base.