XAS/DRIFTS/MS spectroscopy for time-resolved operando investigations at high temperature.

The combination of complementary techniques in the characterization of catalysts under working conditions is a very powerful tool for an accurate and in-depth comprehension of the system investigated. In particular, X-ray absorption spectroscopy (XAS) coupled with diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and mass spectroscopy (MS) is a powerful combination since XAS characterizes the main elements of the catalytic system (selecting the absorption edge) and DRIFTS monitors surface adsorbates while MS enables product identification and quantification. In the present manuscript, a new reactor cell and an experimental setup optimized to perform time-resolved experiments on heterogeneous catalysts under working conditions are reported. A key feature of this setup is the possibility to work at high temperature and pressure, with a small cell dead volume. To demonstrate these capabilities, performance tests with and without X-rays are performed. The effective temperature at the sample surface, the speed to purge the gas volume inside the cell and catalytic activity have been evaluated to demonstrate the reliability and usefulness of the cell. The setup capability of combining XAS, DRIFTS and MS spectroscopies is demonstrated in a time-resolved experiment, following the reduction of NO by Rh nanoparticles supported on alumina.

Benzodiazepine dose reduction in prisoner patients: 15 years' teamwork between psychiatrists and pharmacists.

WHAT IS KNOWN AND OBJECTIVE: Benzodiazepines are widely consumed in prisons, despite the iatrogenic risks associated with this therapeutic class. A multidisciplinary pharmacotherapy programme was therefore initiated by pharmacists in 2001. The aim of this study was to demonstrate the efficacy of teamwork between psychiatrists and pharmacists in benzodiazepine dose adjustment, with 15 years of hindsight. METHOD: In this retrospective study, daily prescribed benzodiazepine doses were compared between a reference group of patients in prisons in Lyon, France, in 2000, and four groups after psychiatrist-pharmacist teamwork in 2004, 2008, 2012 and 2016. RESULTS AND DISCUSSION: A number of 1249 patients were included. Prescribed doses of benzodiazepine decreased in the intervention groups, to a mean of 29-35 mg diazepam equivalent per day, compared to the control group (42 mg/day) (P < .001). The first 4-year period (2000-2004) demonstrated that monthly meetings and systematic pharmaceutical medication review had an impact on prescribed benzodiazepines, limiting consumed doses. The others (2004-2008, 2008-2012 and 2012-2016) confirmed that physicians' adherence to prescription guidelines and the efficacy of pharmacotherapy programme was maintained, particularly in those inmates taking high doses. WHAT IS NEW AND CONCLUSION: A continuous quality programme conducted by psychiatrists and pharmacists showed positive impact in reducing doses of benzodiazepine prescribed to prisoner patients and contributing to reduce risk of benzodiazepine-related problems.

Towards quantitative root hydraulic phenotyping: novel mathematical functions to calculate plant-scale hydraulic parameters from root system functional and structural traits.

Predicting root water uptake and plant transpiration is crucial for managing plant irrigation and developing drought-tolerant root system ideotypes (i.e. ideal root systems). Today, three-dimensional structural functional models exist, which allows solving the water flow equation in the soil and in the root systems under transient conditions and in heterogeneous soils. Yet, these models rely on the full representation of the three-dimensional distribution of the root hydraulic properties, which is not always easy to access. Recently, new models able to represent this complex system without the full knowledge of the plant 3D hydraulic architecture and with a limited number of parameters have been developed. However, the estimation of the macroscopic parameters a priori still requires a numerical model and the knowledge of the full three-dimensional hydraulic architecture. The objective of this study is to provide analytical mathematical models to estimate the values of these parameters as a function of local plant general features, like the distance between laterals, the number of primaries or the ratio of radial to axial root conductances. Such functions would allow one to characterize the behaviour of a root system (as characterized by its macroscopic parameters) directly from averaged plant root traits, thereby opening new possibilities for developing quantitative ideotypes, by linking plant scale parameters to mean functional or structural properties. With its simple form, the proposed model offers the chance to perform sensitivity and optimization analyses as presented in this study.

Small molecules demonstrate the role of dynamin as a bi-directional regulator of the exocytosis fusion pore and vesicle release.

Hormones and neurotransmitters are stored in specialised vesicles and released from excitable cells through exocytosis. During vesicle fusion with the plasma membrane, a transient fusion pore is created that enables transmitter release. The protein dynamin is known to regulate fusion pore expansion (FPE). The mechanism is unknown, but requires its oligomerisation-stimulated GTPase activity. We used a palette of small molecule dynamin modulators to reveal bi-directional regulation of FPE by dynamin and vesicle release in chromaffin cells. The dynamin inhibitors Dynole 34-2 and Dyngo 4a and the dynamin activator Ryngo 1-23 reduced or increased catecholamine released from single vesicles, respectively. Total internal reflection fluorescence (TIRF) microscopy demonstrated that dynamin stimulation with Ryngo 1-23 reduced the number of neuropeptide Y (NPY) kiss-and-run events, but not full fusion events, and slowed full fusion release kinetics. Amperometric stand-alone foot signals, representing transient kiss-and-run events, were less frequent but were of longer duration, similarly to full amperometric spikes and pre-spike foot signals. These effects are not due to alterations in vesicle size. Ryngo 1-23 action was blocked by inhibitors of actin polymerisation or myosin II. Therefore, we demonstrate using a novel pharmacological approach that dynamin not only controls FPE during exocytosis, but is a bi-directional modulator of the fusion pore that increases or decreases the amount released from a vesicle during exocytosis if it is activated or inhibited, respectively. As such, dynamin has the ability to exquisitely fine-tune transmitter release.

Presence of plicidentine in the oral teeth of the coelacanth Latimeria chalumnae Smith 1939 (Sarcopterygii; Actinistia).

The extant coelacanth Latimeria is a sarcopterygian predatory fish with caniniform teeth on its upper and lower jaws. The teeth are constituted of a cone of dentine with an apical cap of enamel, and they are fixed to the osseous component of the jaws by an attachment bone. Internal walls of the tooth base show folds that have been firstly interpreted in the past as radial vascular canals. Three-dimensional visualisation of these foldings using X-ray tomographic techniques and new histological interpretation lead to reconsider these structures as true plicidentine. The folds of the dentine do not invade the whole pulp cavity of the tooth contrary to the plicated condition of most fossil sarcopterygian fishes (e.g., Eusthenopteron, Porolepis, Megalichthys) certain fossil marine reptiles (ichthyosaurs) and extant varanids; in Latimeria they are limited to the lower third to the half of the pulp cavity. The presence of plicidentine in Latimeria's teeth is proposed to be a plesiomorphic character for sarcopterygians.

Assessment of coinfection of sexually transmitted pathogen microbes by use of the anyplex II STI-7 molecular kit.

Anyplex STI-7 is a new molecular kit that detects seven sexually transmitted pathogens. Among 202 subjects screened for genital infection, 143 (70.4%) were diagnosed with at least one pathogen, in concordance with reference methods. In addition, the Anyplex STI-7 demonstrated coinfections, such as that with Ureaplasma parvum and Chlamydia trachomatis, in young women.

ESMO expert consensus statements on the screening and management of financial toxicity in patients with cancer.

BACKGROUND: Financial toxicity, defined as both the objective financial burden and subjective financial distress from a cancer diagnosis and its treatment, is a topic of interest in the assessment of the quality of life of patients with cancer and their families. Current evidence implicates financial toxicity in psychosocial, economic and other harms, leading to suboptimal cancer outcomes along the entire trajectory of diagnosis, treatment, supportive care, survivorship and palliation. This paper presents the results of a virtual consensus, based on the evidence base to date, on the screening and management of financial toxicity in patients with and beyond cancer organized by the European Society for Medical Oncology (ESMO) in 2022. METHODS: A Delphi panel of 19 experts from 11 countries was convened taking into account multidisciplinarity, diversity in health system contexts and research relevance. The international panel of experts was divided into four working groups (WGs) to address questions relating to distinct thematic areas: patients with cancer at risk of financial toxicity; management of financial toxicity during the initial phase of treatment at the hospital/ambulatory settings; financial toxicity during the continuing phase and at end of life; and financial risk protection for survivors of cancer, and in cancer recurrence. After comprehensively reviewing the literature, statements were developed by the WGs and then presented to the entire panel for further discussion and amendment, and voting. RESULTS AND DISCUSSION: A total of 25 evidence-informed consensus statements were developed, which answer 13 questions on financial toxicity. They cover evidence summaries, practice recommendations/guiding statements and policy recommendations relevant across health systems. These consensus statements aim to provide a more comprehensive understanding of financial toxicity and guide clinicians globally in mitigating its impact, emphasizing the importance of further research, best practices and guidelines.

Lipid dynamics in exocytosis.

Regulated exocytosis of neurotransmitter- and hormone-containing vesicles underpins neuronal and hormonal communication and relies on a well-orchestrated series of molecular interactions. This in part involves the upstream formation of a complex of SNAREs and associated proteins leading to the eventual fusion of the vesicle membrane with the plasma membrane, a process that enables content release. Although the role of lipids in exocytosis is intuitive, it has long been overlooked at least compared to the extensive work on SNAREs. Here, we will present the latest advances in this rapidly developing field revealing that lipids actually play an active role in exocytosis by focusing on cholesterol, 3'-phosphorylated phosphoinositides and phosphatidic acid.

10th survey of antimicrobial resistance in noninvasive clinical isolates of Streptococcus pneumoniae collected in Belgium during winter 2007-2008.

OBJECTIVES: The aim of the study was to evaluate the antibiotic resistance in noninvasive clinical isolates of Streptococcus pneumoniae collected in Belgium during winter 2008-2007. METHOD: Four hundred and forty eight unduplicated isolates collected by 15 laboratories were tested by microdilution following CLSI. RESULTS: Insusceptibility rates (I+R) were as follows: penicillin G (PEN) 11.6% (4.0% R), ampicillin 11.4% (4.0% R), amoxicillin+/-clavulanic acid 0, cefaclor 10.3% (9.6% R), cefuroxime 9.2% (8.7% R), cefuroxime-axetil 8.7% (7.8% R), cefotaxime, ceftazidime and cefepime 2.0% (0% R), imipenem 2.5% (0% R), ciprofloxacin and ofloxacin 5.1% (0.4% R), levofloxacin 0.7% (0.4% R), moxifloxacin 0.4% (0.2% R), erythromycin (ERY) 29.7% (29.2% R), azithromycin 29.7% (28.8% R), telithromycin 0%, clindamycin 26.3% (25.4% R) and tetracycline (TET) 21.9% (16.5% R). From 2001 to 2008, a significant decrease in penicillin-insusceptibility (21.0% to 11.6%), penicillin-resistance (9.7% to 4.0%) and ciprofloxacin-insusceptibility (11.2% to 5.1%) was found. Cross-resistance between penicillin and other betalactams in penicillin-insusceptible isolates was incomplete: all these isolates remained fully susceptible to amoxicillin. Erythromycin-insusceptibility was significantly higher in children than in adults (43.9%/27.4%), while penicillin-insusceptibility significantly higher in Brussels than in the Flanders (22.9%/8.1%). The commonest resistance phenotype was ERY-TET (12.7%) followed by ERY (7.4%) and PEN-ERY-TET (5.8%). Capsular types 19 (25%), 14 (19.3%), 23 (15.4%) and 15 (13.5%) were the most important in penicillin-insusceptible. CONCLUSION: We noted a decrease in resistance to the majority of the compounds. Insusceptibility rates were higher in children than in adults and the difference between the north and the south of Belgium became less marked.

Determination of Escherichia coli phylogroups in elderly patients with urinary tract infection or asymptomatic bacteriuria.

OBJECTIVES: Distinguishing between urinary tract infection (UTI) and asymptomatic bacteriuria (ABU) is difficult in the geriatric population since specific symptoms are often lacking. Escherichia coli is the most frequent UTI pathogen in this population but also a common urine colonizer. We hypothesized that detecting E. coli phylogroups B2 or D, which were previously associated with virulent strains responsible for extra-intestinal infections outside elderly patients, could help in distinguishing UTI from ABU. METHODS: Consecutive cases of E. coli bacteriuria diagnosed in hospitalized patients >75 years old during 3 months were investigated for E. coli phylogroups. Multiplex PCR was used to search for several virulence genes as previously described. Characteristics of UTI and ABU cases, assessed retrospectively according to definitions and geriatric expertise, were compared. RESULTS: Out of 233 bacteriuria cases, 60 were assessed to be UTI and 163 to be ABU, with 10 cases unclassified. E. coli strains belonging to the phylogroups B2 and D were significantly more frequent in UTI (48/60, 80%) than in ABU (101/163, 62%) by univariate and multivariate analyses (OR 3.05, 1.44-6.86, p 0.005). Out of all the host and bacterial characteristics studied, falls (p 0.032), comorbidities (p 0.041), and altered autonomy evaluated by a low activity of daily living score (p 0.027) were also associated with UTI using univariate and multivariate analysis. CONCLUSIONS: Determination of the E. coli phylogroup, in addition to some host characteristics, can help to distinguish UTI from ABU in elderly patients with bacteriuria. If this hypothesis is confirmed by prospective studies, then inappropriate use of antibiotics may be reduced in ABU cases.

Phosphoinositides as key regulators of synaptic function.

Phosphoinositides have recently emerged as key regulators of a variety of synaptic processes, including neurosecretory vesicle targeting, exo-endocytosis, and ion channel modulation. These pleiotropic activities derive from their ability to serve either as membrane targeting sites for cytosolic factors, as allosteric ligands, or as nucleation points for coat proteins and cytoskeletal elements. This versatility depends upon the existence of highly diversified enzymatic machinery for their synthesis and degradation, which governs, both temporally and spatially, their appearance in the microenvironment of the synapse.

A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation.

Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer. We show that the GHRP495T variant located in the receptor intracellular domain is able to prolong the GH signal in vitro using stably expressing mouse pro-B-cell and human lung cell lines. This is relevant because GH secretion is pulsatile, and extending the signal duration makes it resemble autocrine GH action. Signal duration for the activated GHR is primarily controlled by suppressor of cytokine signalling 2 (SOCS2), the substrate recognition component of the E3 protein ligase responsible for ubiquitinylation and degradation of the GHR. SOCS2 is induced by a GH pulse and we show that SOCS2 binding to the GHR is impaired by a threonine substitution at Pro 495. This results in decreased internalisation and degradation of the receptor evident in TIRF microscopy and by measurement of mature (surface) receptor expression. Mutational analysis showed that the residue at position 495 impairs SOCS2 binding only when a threonine is present, consistent with interference with the adjacent Thr494. The latter is key for SOCS2 binding, together with nearby Tyr487, which must be phosphorylated for SOCS2 binding. We also undertook nuclear magnetic resonance spectroscopy approach for structural comparison of the SOCS2 binding scaffold Ile455-Ser588, and concluded that this single substitution has altered the structure of the SOCS2 binding site. Importantly, we find that lung BEAS-2B cells expressing GHRP495T display increased expression of transcripts associated with tumour proliferation, epithelial-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2 h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.

[Effectiveness of erlotinib in Critical Care Unit in patients with non-small cell lung cancer with EGFR mutation]. / Efficacité de l'erlotinib en réanimation chez les patients présentant un cancer bronchique non à petites cellules avec une mutation de l'EGFR.

INTRODUCTION: The search for mutations epidermal growth factor receptor (EGFR) has changed the therapeutic approach and prognosis of non-small cell lung cancer (NSCLC). The effectiveness of tyrosine kinase inhibitors (TKI) has been demonstrated orally in patients with EGFR mutation. We report the case of a patient for whom treatment with TKI was started effectively in a Critical Care Unit. OBSERVATION: A patient of 59 years is followed for a stage IV lung adenocarcinoma with metastases in liver, brain, adrenal, lung and pleura. After a first course of chemotherapy (cisplatin-gemcitabine), the patient presents a multi-factorial acute respiratory distress. Due to an EGFR mutation, transfer to intensive care is decided then orotracheal intubation with mechanical ventilation. It is decided to initiate treatment with erlotinib via nasogastric tube. The evolution will be marked by a tumor response leading to a favorable issue. CONCLUSIONS: This case shows the value of initiate TKI despite hospitalization in Intensive Care Unit and highlights the question of the transfer in ICU patients with EGFR mutation.

Pneumocystis carinii pneumonia in cancer patients.

Concern has been arisen about the recently reported increasing incidence of PCP in patients with cancer and the potential transmissibility of this infection. Whether or not there is an increase in the incidence of P. carinii infections, PCP should be considered in the differential diagnosis of pulmonary infiltrates in bone marrow transplant recipients, in patients with hematologic neoplasms and in patients with primary or metastatic brain neoplasms. Intensity of immunosuppression plays a crucial role, especially long-term (> 2 months) corticosteroid treatment. PCP is usually manifested clinically during augmentation or during tapering of corticosteroid dose. Thus, if the chest radiograph of a high-risk patient shows diffuse infiltrates, bronchoscopy and bronchoalveolar lavage should be done immediately. Treatment options are the same as for the AIDS population, except that TMP-SMX is tolerated better in non-AIDS patients. The role of supportive care, including mechanical ventilation in such patients should not be underestimated. Oral therapy with dapsone-trimethoprim or with atovaquone, can be as effective as conventional therapy in mild disease, permitting treatment on an outpatient basis. PCP is often preventable and our understanding has improved about when prophylaxis should be initiated. In the future, the emergence of new technologies for diagnosis and of new agents for treatment and prophylaxis, will bring us closer to the goal of controlling this serious infection.

A 15 kDa proteolipid found in mediatophore preparations from Torpedo electric organ presents high sequence homology with the bovine chromaffin granule protonophore.

Upon SDS PAGE of isolated mediatophore, an acetylcholine-translocating protein, a doublet at 15 kDa was identified. Amino acid sequencing after CNBr cleavage gave a 17 residue-long peptide completely homologous with a sequence of the proton-translocating proteolipid from bovine chromaffin granules. A 51-mer oligodeoxynucleotide corresponding to this sequence was used to screen a library of electric lobe cDNAs constructed in lambda Zap II. A positive recombinant clone was isolated and found to encode the complete sequence of a 15.5 kDa protein highly homologous to the bovine chromaffin or yeast vacuolar ATPase proteolipid. In vitro translation of sense RNA transcripts of the clone indeed yielded a single 15 kDa proteolipid. Northern blot analysis showed that the 1.3 kb mRNA encoding this protein is significantly expressed in nervous tissues but not in electric organ or liver of Torpedo marmorata.

Cloning and expression of the vesamicol binding protein from the marine ray Torpedo. Homology with the putative vesicular acetylcholine transporter UNC-17 from Caenorhabditis elegans.

Complementary DNA clones corresponding to a messenger RNA encoding a 56 kDa polypeptide have been obtained from Torpedo marmorata and Torpedo ocellata electric lobe libraries, by homology screening with a probe obtained from the putative acetylcholine transporter from the nematode Caenorhabditis elegans. The Torpedo proteins display approximately 50% overall identity to the C. elegans unc-17 protein and 43% identity to the two vesicle monoamine transporters (VMAT1 and VMAT2). This family of proteins is highly conserved within 12 domains which potentially span the vesicle membrane, with little similarity within the putative intraluminal glycosylated loop and at the N- and C-termini. The approximately 3.0 kb mRNA species is specifically expressed in the brain and highly enriched in the electric lobe of Torpedo. The Torpedo protein, expressed in CV-1 fibroblast cells, possesses a high-affinity binding site for vesamicol (Kd = 6 nM), a drug which blocks in vitro and in vivo acetylcholine accumulation in cholinergic vesicles.

Achievements and goals of the EORTC Invasive Fungal Infections Group. European Organisation for Research and Treatment of Cancer.

Invasive fungal infections are an increasing complication for patients with cancer. These infections still are difficult to diagnose and to treat and thus still have a high fatality rate. New strategies should include evaluation of new diagnosis tools and large-scale assessment of these new methods will need multidisciplinary collaboration. High-quality clinical trials dedicated to establish 'state-of-the-art' prevention and treatment are also directly needed. Created in 1991, the EORTC Invasive Fungal Infection Group has faced several of these challenges and significantly improved the knowledge and management of these infections in Europe.

Factors associated with bacteraemia in febrile, granulocytopenic cancer patients. The International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC).

The objective of this investigation was to determine factors predictive of bacteraemia at presentation in febrile, granulocytopenic cancer patients in order to estimate the probability of bacteraemia in each patient, and to compare factors associated with a diagnosis of gram-positive or gram-negative bacteraemia. Retrospective analysis of two sets of data (derivation and validation sets) randomly obtained from a large prospective study was conducted in a multicentre study of febrile, granulocytopenic cancer patients admitted for empiric antibacterial therapy. Within the derivation set, prognostic factors (clinical and laboratory data) likely to be associated with a generic diagnosis of bacteraemia and with a specific diagnosis of gram-positive or gram-negative bacteraemia were analysed by means of three backward, stepwise, logistic regression analyses. The predictive probability of bacteraemia was calculated using the logistic equation. The discriminating ability of the model in predicting bacteraemia was evaluated in the derivation and validation sets using receiver-operating characteristic curves. The predictive probability of gram-positive or gram-negative bacteraemia was not calculated. In the derivation set, 157 of 558 episodes (28%) were microbiologically documented bacteraemias. Predicting factors were antifungal prophylaxis, duration of granulocytopenia before fever, platelet count, highest fever, shock and presence and location of initial signs of infection. The variables institution, antibacterial prophylaxis and underlying disease showed borderline associations with bacteraemia. Shock was associated with gram-negative bacteraemia, while signs of infection at catheter site were predictive of gram-positive bacteraemia. Quinolone prophylaxis was negatively associated with gram-negative bacteraemia. When tested in the validation set, the model was poorly predictive, although a small subgroup of episodes (representing only 16% of the total sample size) with low risk of bacteraemia was identified. Factors predictive of bacteraemia can be identified, with discrimination between gram-positive and gram-negative aetiology. Further studies are warranted in order to improve the discriminant ability of the model.

Caring About Women and Cancer (CAWAC): a European survey of the perspectives and experiences of women with female cancers.

This paper reports on the findings of the largest ever European survey of female patients' perceptions of their cancer treatment. It has provided clarification of what women consider important in relation to their management and has identified several areas where more research is needed. It has shown that women's knowledge about cancer before diagnosis is poor and the number undergoing regular screening could be improved. Women are not being adequately prepared and educated about what to expect from treatment and steps should be taken as a matter of urgency to redress this shortcoming. It was revealed that whilst families were the primary source of support to female cancer patients, women also derive considerable support from healthcare professionals, particularly senior doctors; more attention should be paid by specialists and nurses to developing psychological skills to cope with this. In this context, further research is needed into how support groups may best meet patient needs.

Fluconazole treatment of fungal infections in the immunocompromised host.

Immunocompromised patients are predisposed to opportunistic fungal infections. Candidiasis is reported most frequently both as a localized infection (eg, oropharyngeal candidiasis) and as life-threatening systemic candidiasis. With relatively few antifungal agents in the clinical armamentarium, the optimal management of candidiasis remains controversial. Among the agents that are available, amphotericin B is difficult to administer, 5-fluorocytosine cannot be used alone due to the frequent emergence of resistant yeasts, and ketoconazole, which is effective for esophageal and oropharyngeal candidiasis, is not recommended for systemic candidiasis, especially in granulocytopenic patients. Recently, fluconazole, a new triazole antifungal agent, has been found to be active against Candida spp and is being studied in various clinical settings. In addition to its oral formulation, it is available for intravenous (IV) administration, which is a significant advantage in treating debilitated or noncompliant patients. In a randomized, double-blind study, we compared the efficacy of 100 mg/d oral fluconazole with that of 400 mg/d ketoconazole in cancer patients with oropharyngeal candidiasis. Although clinical and microbiological outcomes were similar for both groups, relapses occurred earlier in ketoconazole- than in fluconazole-treated patients. In another study, we administered fluconazole IV 100 to 300 mg/d to 13 patients, eight of whom had fungemia. Preliminary results are encouraging. Further studies of fluconazole as prophylaxis in granulocytopenic patients and as therapy for documented systemic candidiasis are under way. These studies are expected to define specific indications for fluconazole in immunocompromised patients.