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Marine sediments are among the largest carbon reservoirs on the planet and play a key role in the global cycling of organic matter. Bottom fisheries are the most widespread anthropogenic physical disturbance to seabed habitats, prompting NGOs and governments to act on regulating mobile bottom-contacting fishing gear. However, the scientific evidence of the effects of bottom trawling on sediment biogeochemistry is highly diverse and presents contrasting results. Here we present a global harmonized dataset of 71 independent studies that assess the effects of demersal fisheries on sedimentological (i.e. grain size, porosity) and biogeochemical (i.e. organic carbon, phytopigments, nutrient fluxes) properties: the Demersal fishery Impacts on Sedimentary Organic Matter (DISOM) database (Paradis, 2023; https://doi.org/10.3929/ethz-b-000634336). We identify considerable gaps, namely in the geographical extension of the data; coverage of environmental predictors (i.e. seasons); fishing descriptors such as the availability of true controls, quantification of fishing effort, and distribution of fishing gear types; and biogeochemical variables that study the remineralization of organic matter. Future studies should address these data gaps to enhance the comprehensiveness of the dataset. With this harmonized database, we aim to allow researchers to explore the effects of demersal fisheries in variable environmental settings to disentangle the effects of this disturbance and provide efficient management strategies.

Sediments play an important role in organic matter mineralisation and nutrient recycling, especially in shallow marine systems. Marine ecosystem models, however, often only include a coarse representation of processes beneath the sea floor. While these parameterisations may give a reasonable description of the present ecosystem state, they lack predictive capacity for possible future changes, which can only be obtained from mechanistic modelling. This paper describes an integrated benthic–pelagic ecosystem model developed for the German Exclusive Economic Zone (EEZ) in the western Baltic Sea. The model is a hybrid of two existing models: the pelagic part of the marine ecosystem model ERGOM and an early diagenetic model by Reed et al. (2011). The latter one was extended to include the carbon cycle, a determination of precipitation and dissolution reactions which accounts for salinity differences, an explicit description of the adsorption of clay minerals, and an alternative pyrite formation pathway. We present a one-dimensional application of the model to seven sites with different sediment types. The model was calibrated with observed pore water profiles and validated with results of sediment composition, bioturbation rates and bentho-pelagic fluxes gathered by in situ incubations of sediments (benthic chambers). The model results generally give a reasonable fit to the observations, even if some deviations are observed, e.g. an overestimation of sulfide concentrations in the sandy sediments. We therefore consider it a good first step towards a three-dimensional representation of sedimentary processes in coupled pelagic–benthic ecosystem models of the Baltic Sea.

High-dose levofloxacin was explored in a clinical trial against multidrug-resistant tuberculosis and failed to show increased efficacy. In this study, we used a murine model to explore the efficacy of a dose increase in levofloxacin monotherapy beyond the maximum dose evaluated in humans. A total of 120 4-week-old female BALB/c mice were intravenously infected with 10 6 CFU of Mycobacterium tuberculosis H37Rv wild-type (WT) or isogenic H37Rv mutants harboring GyrA A90V or D94G substitutions; the MICs were 0.25, 4, and 6 µg/mL, respectively. Levofloxacin 250 and 500 mg/kg were given every 12 h (q12h) orally for 4 weeks. Pharmacokinetic parameters were determined after five doses. These two regimens decreased lung bacillary load in mice infected with H37Rv WT but not in mice infected with the A90V and D94G mutants. Levofloxacin 250 mg/kg q12h in mice generated pharmacokinetic parameters equivalent to 1,000 mg/d in humans, whereas 500 mg/kg q12h generated a twofold greater exposure than the highest equivalent dose tested in humans (1,500 mg/d). In our dose-response model, the effective concentration at 50% (EC 50 ) produced an AUC/MIC (AUC 0-24h /MIC) ratio of 167.9 ± 27.5, and at EC 80 it was 281.2 ± 97.3. Based on this model, high-dose levofloxacin regimens above 1,000 mg/d are not expected to cause a significant increase in bactericidal activity. This study suggests no benefit of high-dose levofloxacin above 1,000 mg/d in the treatment of fluoroquinolone-susceptible or -resistant tuberculosis., Competing Interests: The authors declare no conflict of interest.

Cloxacillin and oxacillin are group M penicillins. The therapeutic monitoring of plasma concentrations of these antibiotics and those of their hydroxymethylated metabolites is of great clinical interest, especially in the choice of an adequate dosage allowing an effective treatment while limiting the occurrence of undesirable effects and the development of bacterial resistance. In this context, we conducted this work aiming at developing and validating a method allowing the determination of cloxacillin and oxacillin as well as the identification of their active metabolites in different biological matrices (CSF and plasma) using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry. To do this, we carried out several optimisation tests. Subsequently, we validated our method according to the latest bioanalytical validation recommendations of the European Medicines Agency. The validation results showed that our method is specific and sensitive. We obtained good linearity in the range 0.5 to 100 µg/mL with correlation coefficients above 0.995. The lower limit of quantification was 0.5 µg/mL for each analyte. The method was found to be accurate with repeatability and reproducibility coefficients of variation below 15 %. Our method is also accurate with bias values below 15 %. Recovery values ranged from 87 % to 95 %. Finally, we were able to apply our method to the therapeutic monitoring of the analysed molecules and to identify their active metabolites. Our results suggest that LC-MS shows superiority in the therapeutic monitoring of these antibiotics due to the superiority of specificity shown by this method. This assay method can be routinely used for the daily plasma assays of patients treated with these antibiotics in the context of therapeutic monitoring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Multidrug-resistant Gram-negative bacteria-related infections have become a real public health problem and have exposed the risk of a therapeutic impasse. In recent years, many new antibiotics have been introduced to enrich the therapeutic armamentarium. Among these new molecules, some are mainly of interest for the treatment of the multidrug-resistant infections associated with Pseudomonas aeruginosa (ceftolozane/tazobactam and imipenem/relebactam); others are for carbapenem-resistant infections associated with Enterobacterales (ceftazidime/avibactam, meropenem/vaborbactam); and finally, there are others that are effective on the majority of multidrug-resistant Gram-negative bacilli (cefiderocol). Most international guidelines recommend these new antibiotics in the treatment of microbiologically documented infections. However, given the significant morbidity and mortality of these infections, particularly in the case of inadequate therapy, it is important to consider the place of these antibiotics in probabilistic treatment. Knowledge of the risk factors for multidrug-resistant Gram-negative bacilli (local ecology, prior colonization, failure of prior antibiotic therapy, and source of infection) seems necessary in order to optimize antibiotic prescriptions. In this review, we will assess these different antibiotics according to the epidemiological data.

Voriconazole is one of the most used antifungal azoles against pulmonary aspergillosis. Therapeutic drug monitoring (TDM) of the voriconazole concentration in plasma is recommended in clinical practice guidelines to prevent treatment failure and toxicity. The aim of this study was to evaluate the feasibility and utility of TDM of the voriconazole concentration in the sputum of patients treated for pulmonary aspergillosis. Fifty sputum and 31 plasma samples were analysed with high-performance tandem mass spectrometry (HPLC-MS/MS) in 24 patients included in the study. The voriconazole concentration was simultaneously assessed in the plasma and sputum in 22 samples. The correlation between the sputum and plasma levels was estimated with a univariate linear regression model, and the observed R 2 was 0.86. We determined the following equation, C sputum = 0.45 (C plasma ) + 0.21, which could predict the voriconazole concentration in plasma from sputum. TDM of the voriconazole concentration in sputum is an easy, non-invasive and accurate method with which to evaluate voriconazole exposure in patients with pulmonary aspergillosis.

Venlafaxine is the third most frequently prescribed antidepressant in France the last decade, with about 400,000 daily doses. Therapeutic drug monitoring (TDM) of this medication, by measuring the active moiety venlafaxine (V) and O-desmethylvenlafaxine (ODV), is recommended (level of recommendation 2). However, this antidepressant seems to be the one for which clinicians most often use TDM, much more frequently than escitalopram, which is more prescribed and for which TDM is also recommended. The main goal of this review is to provide an update on the TDM of venlafaxine: its therapeutic interval, its level of recommendation and the origin of its "success". From the literature does not enable to define a therapeutic interval for the active moiety V+ODV, that is to say a steady-state trough concentration allowing a clinical response without toxicity. Nevertheless, a target concentration from 100 to 400μg/L is certainly relevant for the majority of patients without any pharmacodynamic resistance ; though a greater concentration could result in an earlier response or could be required for a clinical response in a minority of patients. A patient with no clinical response despite a concentration greater than 1000μg/L should be proposed another antidepressant. Measurement of the ODV/V ratio is also a useful tool, values below 0.3 usually reflecting a slow metabolizer phenotype for cytochrome P-450 2D6, which is more at risk of adverse effects. Research for this phenotype probably explains many prescriptions for TDM., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Pharmacological and clinical data regarding cefoxitin for the treatment of ESBL-producing Enterobacteriaceae-related infections are limited. We performed a multicentric prospective cohort study to evaluate continuous/prolonged, or intermittent infusion of cefoxitin. We assessed the plasma concentration as a function of the duration of infusion and then performed a simulation of the percentage of patients who would reach the PK/PD targets, set at 100% ƒT > MIC or 100% ƒT >4 MIC . Eighty-one patients were included. All patients were treated with 6 gr./day. MICs to cefoxitin ranged from 0.5 to 64 mg/L. Sixteen (19.7%) patients were infected with strains with cefoxitin MICs ≥ 8 mg/L. In all patients infected with strains with MICs ≤ 6 mg/L, PK/PD objectives (100% ƒT > MIC ) were achieved with prolonged or continuous infusion. In contrast, when MICs were 8 mg/L only, continuous infusion was sufficient to achieve the PK/PD objectives (100% ƒT > MIC ). Extended infusion of cefoxitin is necessary for the treatment of non-UTI ESBL-related infections.

Purpose: Currently, four-dimensional (4D) cone-beam computed tomography (CBCT) requires a 3-4 min full-fan scan to ensure usable image quality. Recent advancements in sparse-view 4D-CBCT reconstruction have opened the possibility to reduce scan time and dose. The aim of this study is to provide a common framework for systematically evaluating algorithms for 4D-CBCT reconstruction from a 1-min scan. Using this framework, the AAPM-sponsored SPARE Challenge was conducted in 2018 to identify and compare state-of-the-art algorithms., Methods: A clinically realistic CBCT dataset was simulated using patient CT volumes from the 4D-Lung database. The selected patients had multiple 4D-CT sessions, where the first 4D-CT was used as the prior CT, and the rest were used as the ground truth volumes for simulating CBCT projections. A GPU-based Monte Carlo tool was used to simulate the primary, scatter, and quantum noise signals. A total of 32 CBCT scans of nine patients were generated. Additional qualitative analysis was performed on a clinical Varian and clinical Elekta dataset to validate the simulation study. Participants were blinded from the ground truth, and were given 3 months to apply their reconstruction algorithms to the projection data. The submitted reconstructions were analyzed in terms of root-mean-squared-error (RMSE) and structural similarity index (SSIM) with the ground truth within four different region-of-interests (ROI) - patient body, lungs, planning target volume (PTV), and bony anatomy. Geometric accuracy was quantified as the alignment error of the PTV., Results: Twenty teams participated in the challenge, with five teams completing the challenge. Techniques involved in the five methods included iterative optimization, motion-compensation, and deformation of the prior 4D-CT. All five methods rendered significant reduction in noise and streaking artifacts when compared to the conventional Feldkamp-Davis-Kress (FDK) algorithm. The RMS of the three-dimensional (3D) target registration error of the five methods ranged from 1.79 to 3.00 mm. Qualitative observations from the Varian and Elekta datasets mostly concur with those from the simulation dataset. Each of the methods was found to have its own strengths and weaknesses. Overall, the MA-ROOSTER method, which utilizes a 4D-CT motion model for temporal regularization, had the best and most consistent image quality and accuracy., Conclusion: The SPARE Challenge represents the first framework for systematically evaluating state-of-the-art algorithms for 4D-CBCT reconstruction from a 1-min scan. Results suggest the potential for reducing scan time and dose for 4D-CBCT. The challenge dataset and analysis framework are publicly available for benchmarking future reconstruction algorithms., (© 2019 American Association of Physicists in Medicine.)

Up to 25% of hospitalized patients in a psychiatric department exhibit troubles linked to cannabis use. Weaning patients with psychiatric disorders off drugs of abuse requires specific care to improve their clinical outcome. The present study aims to develop a predictive model of urinary excretion of creatinine-normalized cannabinoids (U CNC ) and to determine U CNC thresholds corresponding to the widely used cut-offs of 20 ng/mL and 50 ng/mL for cannabinoids. One hundred thirty-two patients with 452 urine samples were included between 2013 and 2017. Urinary cannabinoids and U CNC elimination curves were computed for each patient. Using a mono-exponential mixed effect model with 88 samples from 26 subjects exhibiting at least 3 decreasing U CNC in a row, the average calculated elimination rate constant was 0.0108 ± 0.0026 h -1 , corresponding to a mean elimination half-life of 64 ± 12 hours. The use of U CNC is of particular interest because of a high inter- and intra-individual variability of urinary creatinine concentration (from 0.06 to 3.81 mg/mL). Moreover, U CNC allows for the detection of diluted or concentrated urine specimens that may lead to false positive (FP) or false negative (FN) results. Receiver operator characteristic (ROC) curves were used to assess U CNC thresholds of 32.4 and 124.7 ng/mg that provide a strong discrimination between positive and negative samples for cannabinoids cut-offs of 20 and 50 ng/mL respectively. The developed model and the defined U CNC thresholds allowed for the accurate prediction of the time needed to reach a negative U CNC result that could be used by clinicians to optimize clinical care., (© 2019 John Wiley & Sons, Ltd.)

Stability data of toxics or drugs in gel-based or mechanical separation blood collection tubes are lacking, especially for therapeutic drug monitoring and clinical toxicology procedures. According to ISO 15189 accreditation standard, laboratories need to master the entire preanalytical process including the stability of analytes in a specific tube. Here we explored the impact of BD PST™ II and Barricor™ separator tubes on the stability of 167 therapeutic compounds and common drugs of abuse in plasma samples using LC-MS/MS. Forty drugs were significantly affected by the use of PST™ II tubes, including antidepressants (11/26), neuroleptics (9/13), cardiovascular drugs (5/26), anxiolytics and hypnotics (4/25) and some drugs of abuse (5/26). Six compounds exhibited significant reduction by the mechanical Barricor™ tubes. Ten drugs exhibited low (<85%) but non-significant recoveries due to inter-assay variability. Besides, a logP > 3.3 was determined as a cut-off value to predict a potential lack of stability in PST™ II gel tubes with an 86.4% sensitivity and a 61.4% specificity. As a consequence, determination of drugs with a logP > 3.3 should be carried out with caution in plasma samples withdrawn on PST™ II. The study showed the Barricor™ and non-gel tubes cause less drug interference and are recommended for the drugs studied., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Over the last decade, dual-energy CT scanners have gone from prototypes to clinically available machines, and spectral photon counting CT scanners are following. They require a specific reconstruction process, consisting of two steps: material decomposition and tomographic reconstruction. Image-based methods perform reconstruction, then decomposition, while projection-based methods perform decomposition first, and then reconstruction. As an alternative, 'one-step inversion' methods have been proposed, which perform decomposition and reconstruction simultaneously. Unfortunately, one-step methods are typically slower than their two-step counterparts, and in most CT applications, reconstruction time is critical. This paper therefore proposes to compare the convergence speeds of five one-step algorithms. We adapted all these algorithms to solve the same problem: spectral photon-counting CT reconstruction from five energy bins, using a three materials decomposition basis and spatial regularization. The paper compares a Bayesian method which uses non-linear conjugate gradient for minimization (Cai et al 2013 Med. Phys. 40 111916-31), three methods based on quadratic surrogates (Long and Fessler 2014 IEEE Trans. Med. Imaging 33 1614-26, Weidinger et al 2016 Int. J. Biomed. Imaging 2016 1-15, Mechlem et al 2018 IEEE Trans. Med. Imaging 37 68-80), and a primal-dual method based on MOCCA, a modified Chambolle-Pock algorithm (Barber et al 2016 Phys. Med. Biol. 61 3784). Some of these methods have been accelerated by using μ-preconditioning, i.e. by performing all internal computations not with the actual materials the object is made of, but with carefully chosen linear combinations of those. In this paper, we also evaluated the impact of three different μ-preconditioners on convergence speed. Our experiments on simulated data revealed vast differences in the number of iterations required to reach a common image quality objective: Mechlem et al (2018 IEEE Trans. Med. Imaging 37 68-80) needed ten iterations, Cai et al (2013 Med. Phys. 40 111916-31), Long and Fessler (2014 IEEE Trans. Med. Imaging 33 1614-26) and Weidinger et al (2016 Int. J. Biomed. Imaging 2016 1-15) several hundreds, and Barber et al (2016 Phys. Med. Biol. 61 3784) several thousands. We also sum up other practical aspects, like memory footprint and the need to tune extra parameters.

Four-dimensional cone-beam computed tomography (4D-CBCT) of the free-breathing thorax is a valuable tool in image-guided radiation therapy of the thorax and the upper abdomen. It allows the determination of the position of a tumor throughout the breathing cycle, while only its mean position can be extracted from three-dimensional CBCT. The classical approaches are not fully satisfactory: respiration-correlated methods allow one to accurately locate high-contrast structures in any frame, but contain strong streak artifacts unless the acquisition is significantly slowed down. Motion-compensated methods can yield streak-free, but static, reconstructions. This work proposes a 4D-CBCT method that can be seen as a trade-off between respiration-correlated and motion-compensated reconstruction. It builds upon the existing reconstruction using spatial and temporal regularization (ROOSTER) and is called motion-aware ROOSTER (MA-ROOSTER). It performs temporal regularization along curved trajectories, following the motion estimated on a prior 4D CT scan. MA-ROOSTER does not involve motion-compensated forward and back projections: the input motion is used only during temporal regularization. MA-ROOSTER is compared to ROOSTER, motion-compensated Feldkamp-Davis-Kress (MC-FDK), and two respiration-correlated methods, on CBCT acquisitions of one physical phantom and two patients. It yields streak-free reconstructions, visually similar to MC-FDK, and robust information on tumor location throughout the breathing cycle. MA-ROOSTER also allows a variation of the lung tissue density during the breathing cycle, similar to that of planning CT, which is required for quantitative post-processing.