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Objectives: Temocillin is a β-lactam antibiotic used for preventing or treating bacterial infections in liver-transplanted children. We characterized its pharmacokinetics in plasma and ascitic fluid and proposed dosing regimens that maximize achievement of effective drug exposures in this patient group., Methods: Patients aged 6-36 months received 25 mg/kg/12h (n=14) or 25 mg/kg/8h (n=23). Total and unbound temocillin concentrations were measured in plasma and ascitic fluid. Drug safety was monitored. Non-compartmental and population pharmacokinetic analyses were performed, together with Monte-Carlo simulations., Results: No safety concerns were reported. For 25 mg/kg/12h, the unbound mean (±SD) C max and C min were 38±16 and 2±1 mg/L, respectively. For the 25 mg/kg/8h dose, the unbound C max remained similar although the mean C min increased to 5±3 mg/L. Protein binding was saturable. Median penetration in ascitic fluid from plasma was 82% (min-max: 63-95%). A three-compartment model with first order elimination best described unbound pharmacokinetic profiles in plasma and ascitic fluid, with body weight and eGFR as significant covariates. Monte-Carlo simulations suggested that 90% Probability of Target Attainment (PTA) was achieved in both fluids with 25 mg/kg/12h for MICs ≤4 mg/L, eGFR ≤180 mL/min/1.73m 2 or weight ≥6 kg, and with 25 mg/kg/8h, for MICs ≤8 mg/L, GFR ≤120mL/min/1.73m 2 or weight ≥11 kg., Conclusions: Although adequate in many instances, the current dosing regimen is likely inadequate for patients with low body weight, high renal function, or bacteria with high MIC, emphasizing the need for patient-specific factors to be considered in dose selection. These data support the importance of paediatric pharmacokinetic studies to optimize drug dosing regimens., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The dendrochemical approach holds significant promise for determining the geographical origin of wood as a complementary tool to dendroprovenancing based on tree-ring width. Tracing the origin of wood based on its elemental and isotopic composition is in particular interesting for provenance studies at the regional scale, as dendrochemical signatures are indicative of geological and pedological characteristics. Although, absorption of nutrients and trace elements reflects the composition of soil bioavailable pools, it is also modulated by multiple environmental and tree related factors. We assess the dendrochemical approach in oak wood provenance studies regarding the challenges posed by 1) geochemical variation at a local level, and 2) dendrochemical variation related to oak species, age and social status. A combination of 13 elemental concentrations and 2 isotope - Sr and Nd - ratios was analyzed in oak wood from 12 forests situated in the large Seine river catchment in France. The sampling targeted sites with representative types of geological parent material, where adult trees of two common temperate Quercus species (Quercus petraea and Quercus robur) were selected. The impact of tree characteristics was markedly weaker than that of the site factor and the minimal differences in dendrochemical composition between Quercus petraea and Quercus robur were considered without effect on determination of the geographical origin. Linear discriminant analysis based on Ca-normalized elemental concentrations and Sr and Nd isotope ratios correctly classified the origin of 93 % of the sampled trees. Strontium isotope ratio 87 Sr/ 86 Sr was the strongest provenance indicator capable of determining the origin of 55 % of wood samples on its own. Our system based on elemental and strontium and neodymium isotopic compositions provides robust indicators for wood tracing and might be applied to provenance studies in environment, physiology, history and archeology., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Since their original proposal in 2008, a number of broadly distributed flavoprotein systems catalyzing electron bifurcation have been identified that play key roles in the bioenergetics of anaerobic bacteria and archaea. While the overall thermodynamics of flavin-based electron bifurcation are now quite well-understood, the same cannot be said of their kinetic behavior. The present account represents a summary of results obtained with several electron-electron bifurcating systems, shamelessly focusing on work done in the authors' laboratory., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Tidal marshes are often restored on compact agricultural soil that limits tidally induced groundwater dynamics and soil aeration after restoration. We hypothesized that impaired soil aeration affects biogeochemical cycling and leads to altered porewater nutrient concentrations in restored tidal marshes. We studied soil hydraulic properties, groundwater dynamics and porewater nutrient concentrations (nitrogen, phosphorus and dissolved silica) over the course of one year in a natural and a restored freshwater tidal marsh in the Scheldt estuary, Belgium. From measured groundwater levels, we calculated the soil saturation index (the proportion of time the soil is saturated at a certain depth). The aerated zone generally extends over a deeper soil profile in the natural marsh compared to the restored marsh, where the former agricultural subsoil has a higher compaction rate and lower hydraulic conductivity. The soil saturation index was negatively correlated with nitrate (ρ = -0.21, p < 0.001) and positively correlated with ammonium (ρ = 0.32, p < 0.001). Concentrations of phosphate (ρ = 0.43, p < 0.001) and dissolved iron (ρ = 0.44, p < 0.001) were positively correlated to the soil saturation index, suggesting retention of phosphate on iron oxides in well aerated zones, which are more abundant in the natural marsh. The depth profile of soil hydraulic properties and soil aeration is very site specific, even within the same marsh, suggesting the need for a pre-restoration assessment of soil hydraulic properties to determine where and which design measures are required to optimize nutrient cycling in newly restored tidal marshes., 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 © 2024 Elsevier B.V. All rights reserved.)

Objectives: Despite the good prognosis of surgical treatment of chronic subdural hematomas, there are some early deaths, recurrences and post-operative complications. The objective of this study is to analyze the prognostic factors of chronic subdural hematomas in two reference university teaching hospitals in the city of Yaounde., Method: Three hundred and ten cases of chronic subdural hematomas were diagnosed on 3788 patients hospitalized in the neurosurgery departments of two reference university teaching hospitals in the city of Yaounde from January 1st, 2015 to December 31st, 2021 (7 years). The authors collected data from patients in whom surgical treatment was performed and assessed their prognosis with regard to the rate of early and late recurrence, mortality rate and postoperative complications and associated factors., Results: Data from 284 patients were analyzed. The mortality rate was 6.7 % and the recurrence rate was 3.2 % in early postoperative period and 4.5 % after a follow-up of 3-24 months. Prognostic factors for death were age greater than or equal to 80 years (p value = 0.034) and presence of cortico-subcortical atrophy (p value = 0.003). The main recurrence factors were age greater than or equal to 70 years and compartmentalization of the hematoma., Conclusion: Chronic subdural hematomas are generally of good prognosis when the Glasgow coma score on admission is good and adequate management is carried out as soon as possible. Advanced age, lesions such as cortico-subcortical atrophy and compartmentalization of the hematoma are all factors that predispose to recurrence or early mortality. Those groups of patients should therefore benefit from a closer follow-up in post-operative period., Competing Interests: Declarations of interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The latest report from the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) raises concerns about the global proliferation of non-native species (NIS) driven by increasing temperatures. In 2023, the invasive blue crab Callinectes sapidus experienced a significant range expansion in the French Mediterranean lagoons, now present in over 20 lagoons and numerous estuaries with different invasion gradients. It has been established that this species is eurytherm (tolerates a wide range of temperatures; 0-40 °C), rendering temperature a non-limiting factor for its proliferation. On the other hand, salinity is a critical factor to consider, as C. sapidus requires brackish water for copulation and saline water for egg maturation. In this study, we present the salinity tolerance of C. sapidus using the metabolic performance to define the tolerance of the species to a large range of salinities (13 levels from 0 to 65 psu). Results showed that C. sapidus tolerates a large range of salinities with a minimum critical threshold (CT min ) at 0 psu, an optimum at 18.5 psu, and a CT max at 62.4 psu. Using the performance curve equation, we applied the curve to real salinity data measured each month in 2023 in 20 lagoons invaded. Using this approach, we were able to map, on a fine spatial scale, the distribution of suitable habitats for C. sapidus in the year 2023. Additionally, we have developed a tool to prioritize the lagoons based on their suitability, thereby providing a decision-making framework for management measures in each lagoon. It emerged that 50 % of lagoons were priority areas, 10 % were intermediate and 40 % required monitoring. On the basis of this approach, we can respond to European regulations to help decision-makers implement action plans and/or early detection programs for invasive species management., 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 © 2024 Elsevier B.V. All rights reserved.)

Background: Approximately one-half of the patients with angina and nonobstructive coronary artery disease (ANOCA) have evidence of coronary microvascular dysfunction (CMD)., Objectives: This study aims to characterize patients with ANOCA by measuring their minimal microvascular resistance and to examine the pattern of vascular remodeling associated with these measurements., Methods: The authors prospectively included patients with ANOCA undergoing continuous thermodilution assessment. Lumen volume and vessel-specific myocardial mass were quantified using coronary computed tomography angiography (CTA). CMD was defined as coronary flow reserve <2.5 and high minimal microvascular resistance as >470 WU., Results: A total of 153 patients were evaluated; 68 had CMD, and 22 of them showed high microvascular resistance. In patients with CMD, coronary flow reserve was 1.9 ± 0.38 vs 3.2 ± 0.81 in controls (P < 0.001). Lumen volume was significantly correlated with minimal microvascular resistance (r = -0.59 [95% CI: -0.45 to -0.71]; P < 0.001). In patients with CMD and high microvascular resistance, lumen volume was 40% smaller than in controls (512.8 ± 130.3 mm 3 vs 853.2 ± 341.2 mm 3 ; P < 0.001). Epicardial lumen volume assessed by coronary CTA was independently associated with minimal microvascular resistance (P < 0.001). The predictive capacity of lumen volume from coronary CTA for detecting high microvascular resistance showed an area under the curve of 0.79 (95% CI: 0.69-0.88)., Conclusions: Patients with CMD and high minimal microvascular resistance have smaller epicardial vessels than those without CMD. Coronary CTA detected high minimal microvascular resistance with very good diagnostic capacity. Coronary CTA could potentially aid in the diagnostic pathway for patients with ANOCA., Competing Interests: Funding Support and Author Disclosures Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. Dr Mizukami has received consultancy fees from Zeon Medical Inc, research grants from Boston Scientific, and speaker fees from Abbott Vascular, Cath works, and Boston Scientific. Drs Buytaert and Munhoz have received research grants provided by the Cardiopath PhD program. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Accurate determination of the internal length of nasogastric tubes is essential for the safe and effective completion of blind insertions, a routine nursing procedure. The widely used nose-earlobe-xiphoid distance lacks evidence and effectiveness. A recent randomized controlled trial proposed an alternative, the corrected nose-earlobe-xiphoid distance formula. However, its effectiveness in real-world clinical practice has not yet been studied., Objective: This study assessed the real-world clinical effectiveness of the corrected nose-earlobe-xiphoid distance formula for determining the internal nasogastric tube length in adult patients admitted to hospitalization or intensive care units., Design: A single-center retrospective clinical effectiveness study was conducted, utilizing routinely collected observational data., Setting and Main Outcome Measures: Between October 2020 and November 2022, 358 adult patients in a general hospital requiring a nasogastric feeding tube were included. The primary outcome involved assessing nasogastric tube tip positioning (>3 cm below the lower esophageal sphincter) by an advanced practice nurse through X-ray verification. Secondary outcomes, obtained from patient records for a random subgroup of 100 participants, were reporting clarity and evaluation of the tip position by reviewing radiologists., Results: Following evaluation by an advanced practice nurse, all nasogastric feeding tubes were determined to be correctly positioned. Among the subgroup of 100 tubes, X-ray protocols, as documented by the reviewing radiologists, showed varying levels of reporting clarity for the tube tip: 4.0 % lacked reporting, 33.0 % had ambiguous reporting and 63.0 % had unambiguous reporting., Conclusion: The corrected nose-earlobe-xiphoid distance formula demonstrates potential to emerge as a safer alternative to existing methods for determining the internal length of nasogastric tubes., Implications for Clinical Practice: In addition to healthcare provider education and training, a checklist-based framework is recommended for radiologists to unambiguously report nasogastric tube tip positions., 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 © 2024 Elsevier Ltd. All rights reserved.)

Pyrethroid insecticides are widely detected in aquatic ecosystems due to their extensive use in agriculture and horticulture, which could pose a potential risk to aquatic non-target organisms. While previous ecotoxicological studies have been conducted mainly with standard tests and local species under temperate conditions, scarce information is available on the effects of pyrethroid insecticides on communities and ecosystems under (sub-)tropical conditions. A single application of lambda-cyhalothrin at concentrations of 0, 9, 30, and 100 ng/L was evaluated in outdoor mesocosms under sub-tropical conditions. Lambda-cyhalothrin was found to dissipate rapidly in the water column, with only 11 % and 7 % of the remaining dose measured at 1 and 3 days after application, respectively. Lambda-cyhalothrin concentrations disappeared considerably faster from the water compartment compared to temperate conditions. Consistent decreases in abundance were observed for Lecane lunaris at the medium and higher treatments (NOEC = 9 ng/L) and at the highest treatment (NOEC = 30 ng/L) for Keratella tropica. On the contrary, two taxa belonging to Cladocera (i.e., Ceriodaphnia sp. and Diaphanosoma sp.) showed the most prominent increase in abundance related to the lambda-cyhalothrin treatments. At the community level, a consistent no observed effect concentrations (NOECs) of 9 ng/L could be calculated for the zooplankton community. A marginal significant overall treatment related effect was observed for the macroinvertebrate community. The results of species sensitivity distribution (SSD) analysis based on results of acute toxicity experiments conducted alongside the mesocosm experiment and obtained from the literature indicated that macroinvertebrates from temperate regions may be generally more sensitive than their counterparts in (sub-)tropical regions. Overall, these findings suggest that environmentally relevant concentrations of the pyrethroid insecticide lambda-cyhalothrin may lead to different ecological outcomes in freshwater ecosystems in the (sub-)tropics relative to temperate regions., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Intertidal microphytobenthos (MPB) are a major contributor to primary production in estuarine ecosystems. While their biomass is highly variable at multiple spatial and temporal scales, the underlying drivers are as yet little understood. Both in situ sampling and remote-sensing techniques often lack the temporal resolution or coverage to simultaneously capture short-term (intratidal to daily) and longer-term (weekly to annual) biomass changes. Our field setup with in-situ NDVI sensors allowed us to study MPB surface biomass variability at high temporal resolution (10 mins) for up to two years in a freshwater euglenoid dominated mudflat, and a brackish and a marine diatom dominated mudflat. MPB biomass showed marked periodicities at multiple temporal scales: seasonal, spring-neap and intratidal. The diatom-dominated MPB community showed a seasonal biomass peak in winter, while the euglenoid-dominated community showed biomass peaks during spring and summer, probably caused by underlying divergent responses to mainly irradiance, temperature and wind-induced resuspension, and macrobenthos grazing. Spring-neap periodicity likely resulted from differential migratory responses of the MPB communities to variation in timing and duration of daylight exposure. In the freshwater community, upward migration only occurred when exposure duration was sufficiently long (≥4 h). In the diatom-dominated community, morning daylight exposure resulted in highest NDVI values. This study highlights the differences in MPB biomass dynamics between MPB communities within estuarine ecosystems, and underscores the great potential of high-resolution temporal NDVI monitoring for more accurate estimates of MPB biomass and primary production., 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 article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Bordetella pertussis continues to cause whooping cough globally even in countries with high immunisation coverage. Booster vaccinations with acellular pertussis vaccines are thus used in children, adolescents, and adults. T cell immunity is crucial for orchestrating the immune response after vaccination. However, T cell assays can be expensive and difficult to implement in large clinical trials. In this study, a whole blood (WB) stimulation assay was developed to identify secreted T cell associated cytokines in different age groups after acellular pertussis booster vaccination., Material and Methods: Longitudinal WB samples were collected from a small set of subjects (n = 38) aged 7-70 years participating in a larger ongoing clinical trial. For assay development, samples were diluted and incubated with purified inactivated pertussis toxin (PT), filamentous haemagglutinin (FHA), inactivated B. pertussis lysate, and complete medium (M) as stimulating conditions, with anti-CD28 and anti-CD49d as co-stimulants. Different timepoints around the vaccination (D0, D7, D14, D28), WB dilution factor (1:2, 1:4) and incubation time (24 h, 48 h, 72 h) were compared. Responses to 15 cytokines were tested with Luminex/multiplex immunoassay., Results: The optimized assay consisted of WB incubation with M, PT, and FHA (including the two co-stimulants). After 48 h incubation, supernatants were collected for measurement of seven selected T cell associated cytokines (IL-2, IL-5, IL-10, IL-13, IL-17 A, IL-17F, and IFN-y) from samples before and 28 days after vaccination. PT stimulation showed a trend for upregulation of IL-2, IL-13, and IL-17 A/F for adult subjects, whereas the responses of all cytokines were downregulated for the paediatric subjects. Furthermore, PT and FHA-stimulated WB showed diverse cytokine producing profiles., Conclusions: The developed WB-based cytokine assay was shown to be less costly, easy to perform, and functional in differently aged individuals. Further, it requires only a small amount of fresh blood, which is beneficial especially for studies including infants. Our results support the use of this assay for other immunological studies in the future., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The transcaval (TCv) vascular approach is increasingly used in transcatheter aortic valve replacement (TAVR) in patients unsuitable for the gold-standard transfemoral approach. We aimed to evaluate the efficacy, safety, and clinical outcomes associated with TCv-TAVR., Methods: A systematic review and meta-analysis was conducted by searching PubMed/Medline, Embase, and the Cochrane Library for all articles assessing the TCv approach published through December 2023. Outcomes included 30-day and 1-year all-cause mortality (ACM), 30-day rehospitalisation, perioperative complications and postoperative complications at 30 days. The meta-analysis was registered on the PROSPERO database with the identifier CRD42024501921., Results: A total of 8 studies with 467 patients were included. TCv-TAVR procedures achieved a success rate of 98.5%. TCv-TAVR was associated with a 30-day ACM rate of 6.1% (95% confidence interval [CI]: 3.9%-8.2%), a 1-year ACM rate of 14.9% (95% CI 2.3%-27.6%) and a 30-day rehospitalisation rate of 4.2% (95% CI -2.2% to 10.6%). Postoperative stroke or transient ischemic attack, major vascular complications, and major or life-threatening bleeding occurred in 3.3%, 8.7%, and 7.5% of cases, respectively. Cumulative meta-analyses showed a temporal trend of decreasing rates of vascular complications., Conclusions: The TCv approach in TAVR demonstrated a reassuring efficacy and safety profile, with mortality and postoperative complication rates similar to those reported for supra-aortic alternative TAVR access routes. The temporal decrease in vascular complications suggests potential improvements in procedural techniques and device technology. These findings further support the TCv approach as a viable option in patients ineligible for the transfemoral access., Prospero: CRD42024501921., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

While drought impacts are widespread across the globe, climate change projections indicate more frequent and severe droughts. This underscores the pressing need to increase resistance and resilience to drought. The strategic application of Preventive Drought Management Measures (PDMMs) is a suitable avenue to reduce the likelihood of drought and ameliorate associated damages. In this study, we use an optimisation approach with a multicriteria decision-making method to allocate PDMMs for reducing the severity of agricultural and hydrological droughts. The results indicate that implementing PDMMs can reduce the severity of agricultural and hydrological droughts, and the obtained management scenarios (solutions) highlight the utility of multi-objective optimisation for PDMMs planning. However, examined management scenarios also illustrate the trade-off between managing agricultural and hydrological droughts. PDMMs can alleviate the severity of agricultural droughts while producing opposite effects for hydrological droughts (or vice versa). Furthermore, the impact of PDMMs displays temporal and spatial variabilities. For instance, PDMMs implementation within a specific subbasin may mitigate the severity of one type of drought in a given month yet exacerbate drought conditions in preceding or subsequent months. In the case of hydrological droughts, the PDMMs may intensify streamflow deficits in the intervened subbasins while alleviating the hydrological drought severity downstream (or vice versa). These complexities emphasise a customised implementation of PDMMs, considering the basin characteristics (e.g., rainfall distribution over the year, soil properties, land use, and topography) and the quantification of PDMMs' effect on the severity of each type of drought., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Liquid chromatography coupled with mass spectrometry (LC-MS) has been tremendously used for screening purposes in forensic toxicology, because of their great adaptability and reasonable time/resource consumption. Herein, a fully validated method based on liquid-liquid extraction (LLE) in human whole blood, by a multiple reaction monitoring (MRM) analysis through LC-MS/MS, is described. The proposed method simultaneously detects 100 analytes (plus three deuterated internal standard compounds) belonging to many different classes, including drugs of abuse, prescription and over-the-counter drugs commonly involved in poisoning and medical malpractice cases in our territory, as well as certain new psychoactive substances (NPS) and toxic substances potentially associated with adverse effects. The optimised LLE employs one extraction step of 200 μL blood using 0.1 M HCl methyl-tert-butyl-ether (MTBE) (acidified with concentrated HCl) proved to be suitable for the extraction of basic and neutral substances; as a reconstitution solvent a mixture of 88:12v/v, 0.1 % formic acid in 10 mM aqueous ammonium acetate, pH 3.5: 0.1 % formic acid in acetonitrile was used, yielding satisfactory recoveries for all analytes. The method was sensitive, showing low LOD/ LOQ for all substances ranging from 0.01 to 5/ 0.05-20 ng/mL, respectively. Linearity ranged between 0.05-500 ng/mL (R 2  = 0.9811-0.9995), and the inter- and intra-day precisions ranged between 3-15 % and 7-18 %, respectively. Accuracy was evaluated in terms of percentage recovery, lying within acceptable range. The matrix effect expressed as ion suppression/enhancement of each analyte was in the range ±25 % for all analytes. Post-preparative stability of analytes was higher than 85 %, while no carryover between runs was observed. The developed method has been successfully applied in routine toxicological analyses for the analysis of biological samples from clinical and autopsy cases., 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 © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: We declare no competing interests.

Background: Vulnerable plaque presents prognostic implications in addition to functional significance., Objectives: The aim of this study was to identify relevant features of vulnerable plaque in functionally significant lesions., Methods: In this multicenter, prospective study conducted across 5 countries, including patients who had invasive fractional flow reserve (FFR) ≤0.80, a total of 95 patients with available pullback pressure gradient (PPG) and plaque analysis on coronary computed tomographic angiography and optical coherence tomography were analyzed. Vulnerable plaque was defined as the presence of plaque rupture or thin-cap fibroatheroma on optical coherence tomography. Among the 25 clinical characteristics, invasive angiographic findings, physiological indexes, and coronary computed tomographic angiographic findings, significant predictors of vulnerable plaque were identified., Results: Mean percentage diameter stenosis, FFR, and PPG were 77.8% ± 14.6%, 0.66 ± 0.13, and 0.65 ± 0.13, respectively. Vulnerable plaque was present in 53 lesions (55.8%). PPG and FFR were identified as significant predictors of vulnerable plaque (P < 0.05 for all). PPG >0.65 and FFR ≤0.70 were significantly related to a higher probability of vulnerable plaque after adjustment for each other (OR: 6.75 [95% CI: 2.39-19.1]; P < 0.001] for PPG >0.65; OR: 4.61 [95% CI: 1.66-12.8]; P = 0.003 for FFR ≤0.70). When categorizing lesions according to combined PPG >0.65 and FFR ≤0.70, the prevalence of vulnerable plaque was 20.0%, 57.1%, 66.7%, and 88.2% in the order of PPG ≤0.65 and FFR >0.70, PPG ≤0.65 and FFR ≤0.70, PPG >0.65 and FFR >0.70, and PPG >0.65 and FFR ≤0.70 (P for trend < 0.001), respectively., Conclusions: Among low-FFR lesions, the presence of vulnerable plaque can be predicted by PPG combined with FFR without additional anatomical or plaque characteristics. (Precise Percutaneous Coronary Intervention Plan [P3] Study; NCT03782688)., Competing Interests: Funding Support and Author Disclosures This study received funding from HeartFlow and was also supported by grants from the Patient-Centered Clinical Research Coordinating Center (HI19C0481 and HC19C0305) funded by the Ministry of Health and Welfare and from the Ministry of Food and Drug Safety (RS-2023-00215667), Republic of Korea. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow; and has received speaker fees from Abbott Vascular. Dr Leipsic is a consultant for and holds stock options in Circle CVI and HeartFlow; has received a research grant from GE; and has received modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath PhD program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow. Dr Otake has received research grants from Abbott Vascular; and has received speaker fees from HeartFlow and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordics; and has received institutional research grants from Bayer, Philips Healthcare, and Novo Nordisk. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr De Bruyne has received consulting fees from Boston Scientific and Abbott Vascular; has received research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow, Edwards Lifesciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and has received consulting fees from HeartFlow, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

To solve some scheduling problems of batch processes based on timed Petri net models, timed extended reachability graphs (TERGs) and approximated TERGs can be used. Such graphs abstract temporal specifications and represent parts of timed languages. By exploring the feasible trajectories in a TERG, optimal schedules can be obtained with respect to the makespans of batch processes that are modeled by timed Petri nets. Nevertheless, the rapid growth of the number of states in a TERG makes the problem intractable for large systems. In this paper, we improve the existing clustering TERG approach, and we make it suitable for large sized batch processes. We also enlarge a systematic approach to model batch processes with timed Petri nets. Finally, a comprehensive example of scheduling problem is studied for an archetypal chemical production plant in order to illustrate the efficiency of the proposed approach., 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 © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75 % in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism., Competing Interests: Declaration of competing interest AC declares institutional research funding from Genentech, Merck Serono, BMS, MSD, Roche, Beigene, Bayer, Servier, Lilly, Natera, Novartis, Takeda, Astellas and Fibrogen and advisory board or speaker fees from Merck Serono, Roche, Servier, Takeda and Astellas. NT declares advisory board or speaker fees from Merck Serono, Servier, Pfizer, Natera and Guardant Health. MH declares advisory board and speaker fees from Servier. TF declares institutional research funding from Genentech, Adapt immune, Roche, Beigene, Astelas, BMS, Daichii Sanyo, Amgen and speaker fees from Astrazeneca, Amgen, Bayer, BMS, Lilly, MSD and Servier. VG declares advisory board fees from Boehringer Ingelheim and institutional research funding from Bayer, Boehringer, Roche, Genentech, Merck Serono, Beigene, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, MSD. SR declares personal fees as an invited speaker from Amgen, MSD and Servier. Advisory board fees from Amgen, Servier and Sirtex and institutional funding from Ability Pharmaceuticals, Astellas, G1 Therapeutics, Hutchinson, Menarini, Mirati, Novartis, Pfizer, Pierre Fabre, Roche and Seagen. LS declares advisory board or speaker fees from Johnson and Johnson, Medtronic, Baxter, Cella Medical Solutions. The remaining authors declare no competing interests. All authors have read the journal's policy on disclosure of potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To understand if and why guardians access their adolescent child's electronic health record patient portal account., Methods: Guardians of transgender and gender-diverse adolescents completed a survey regarding patient portal use. Descriptive statistics were used to describe items related to guardian access to adolescent portal accounts., Results: Of 82 respondents, 37.8% indicated they had used their child's login to access the patient portal. Most indicated they accessed their adolescent's account because their child asked them to do so. Other common reasons included being worried they might miss important health information and not realizing there was a difference between patient and proxy accounts., Discussion: Results of this study provide a more detailed understanding regarding guardian access to adolescent patient portals. Findings can be used to inform adolescent patient portal design and enrollment practices that protect adolescent confidentiality., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

The Solanaceae family and the Withania genus specifically are rich sources of medicinal plants. Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS/MS) revealed a predominance of withanolides from an organic extract of Withania obtusifolia. A constructed molecular network uncovered the presence of potentially novel withanolides. A series of withanolides were then isolated and structurally characterized from the extract including two new withanolides (withafolia A and withafolia B) and seven previously reported metabolites. Of the isolated compounds, cytotoxicity of withanolide J, physaperuvin G, and a commercial STAT3 inhibitor (S3I-201) were assessed against a human leukemia HL-60 cell line resulting in IC 50 values of 26, 29, and 120 μM, respectively. In silico molecular docking simulations indicate that withanolide J and physaperuvin G can bind as an inhibitor in the active site of STAT3 with docking scores comparable to the selective STAT3 inhibitor, S3I-201., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paul W Pare reports financial support and equipment, drugs, or supplies were provided by Texas Tech University. If there are other authors, they 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. Published by Elsevier B.V.)

Background: There is lack of data on the association between socioeconomic factors, guidelines compliance and clinical outcomes among patients with acute biliary pancreatitis (ABP)., Methods: Post-hoc analysis of the international MANCTRA-1 registry evaluating the impact of regional disparities as indicated by the Human Development Index (HDI), and guideline compliance on ABP clinical outcomes. Multivariable logistic regression models were employed to identify prognostic factors associated with mortality and readmission., Results: Among 5313 individuals from 151 centres across 42 countries marked disparities in comorbid conditions, ABP severity, and medical procedure usage were observed. Patients from lower HDI countries had higher guideline non-compliance (p < 0.001) and mortality (5.0% vs. 3.2%, p = 0.019) in comparison with very high HDI countries. On adjusted analysis, ASA score (OR 1.810, p = 0.037), severe ABP (OR 2.735, p < 0.001), infected necrosis (OR 2.225, p = 0.006), organ failure (OR 4.511, p = 0.001) and guideline non-compliance (OR 2.554, p = 0.002 and OR 2.178, p = 0.015) were associated with increased mortality. HDI was a critical socio-economic factor affecting both mortality (OR 2.452, p = 0.007) and readmission (OR 1.542, p = 0.046)., Conclusion: These data highlight the importance of collaborative research to characterise challenges and disparities in global ABP management. Less developed regions with lower HDI scores showed lower adherence to clinical guidelines and higher rates of mortality and recurrence., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Distal Cholangiocarcinoma (dCCA) represents a challenge in hepatobiliary oncology, that requires nuanced post-resection prognostic modeling. Conventional staging criteria may oversimplify dCCA complexities, prompting the exploration of novel prognostic factors and methodologies, including machine learning algorithms. This study aims to develop a machine learning predictive model for recurrence after resected dCCA., Material and Methods: This retrospective multicentric observational study included patients with dCCA from 13 international centers who underwent curative pancreaticoduodenectomy (PD). A LASSO-regularized Cox regression model was used to feature selection, examine the path of the coefficient and create a model to predict recurrence. Internal and external validation and model performance were assessed using the C-index score. Additionally, a web application was developed to enhance the clinical use of the algorithm., Results: Among 654 patients, LNR (Lymph Node Ratio) 15, neural invasion, N stage, surgical radicality, and differentiation grade emerged as significant predictors of disease-free survival (DFS). The model showed the best discrimination capacity with a C-index value of 0.8 (CI 95 %, 0.77%-0.86 %) and highlighted LNR15 as the most influential factor. Internal and external validations showed the model's robustness and discriminative ability with an Area Under the Curve of 92.4 % (95 % CI, 88.2%-94.4 %) and 91.5 % (95 % CI, 88.4%-93.5 %), respectively. The predictive model is available at https://imim.shinyapps.io/LassoCholangioca/., Conclusions: This study pioneers the integration of machine learning into prognostic modeling for dCCA, yielding a robust predictive model for DFS following PD. The tool can provide information to both patients and healthcare providers, enhancing tailored treatments and follow-up., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Normal pressure hydrocephalus can be treated with ventriculoperitoneal shunt (VPS) placement, but no broadly implemented indication for VPS exists., Methods: Our protocol consists of physical therapy and occupational therapy practitioners administering validated tests of gait, balance, and cognition before and after lumbar drain placement. Specific tests include: Timed "Up & Go", Tinetti Gait and Balance Assessment, Berg Balance Scale, Mini Mental Status Exam, Trail Making Test Part B, and the Rey Auditory and Visual Learning Test. Minimal clinically important difference values for each test were determined from literature review. A retrospective review of patients treated under this protocol was performed. The primary outcomes were candidacy for VPS based on the protocol and patient-reported symptomatic improvement after VPS placement., Results: A total of 48/75 (64%) patients received VPS. A total of 43/48 (89.6%) of those shunted reported improved symptoms at 6-week follow-up. However, 10/22 (45.5%) reported worsening symptoms at 1-year follow-up. The mean Tinetti score significantly increased after lumbar drain in patients who improved with VPS compared to the no shunt group (4.27 vs. -0.48, P < 0.001). A total of 6/33 (18%) patients with postoperative imaging had a subdural fluid collection identified and 3/49 (6%) had other complications, including 1 seizure, 1 intracerebral hemorrhage, and 1 stroke., Conclusions: Standardized assessment of gait, balance, and cognition before and after temporary cerebrospinal fluid diversion identifies patients with normal pressure hydrocephalus likely to benefit from VPS placement with a low complication rate. One year after VPS, approximately one half of patients had symptoms recurrence., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Sacral neuromodulation (SNM) has evolved as a therapeutic intervention for various pelvic floor dysfunctions. However, the traditional approach primarily assesses discipline-specific symptoms, potentially overlooking holistic symptom improvement. We aimed to investigate whether a more comprehensive evaluation of pelvic floor symptoms enhances the assessment of SNM's test phase., Material and Methods: A prospective single-center trial (Optimization of Lower Urinary Tract Symptoms study) assessed SNM efficacy from March 2018 to December 2021 in patients from the urology department (UD) and colorectal surgery department (CRD) with a follow-up of 12 months. Objective and subjective outcomes were examined using diaries and patient-reported outcome measures. Statistical analyses were conducted to determine predictive factors for treatment success, expressed by the patient global impression of change. SPSS 29.0 was used., Results: A total of 85 participants were included, displaying concomitant pelvic floor symptoms. After the first phase, significant improvements on all pelvic floor domains questionnaires were seen for both patients from UD and those from CRD. Although improvements were observed in bladder and bowel diaries, the traditional criteria for success (≥50% improvement in diary variables) did not consistently correlate with the patients' global impression of change. The absolute reductions in bother sum scores from multiple domains were significant predictors for the patients' global impression of change, outperforming discipline-specific assessments. Patients from UD benefit from both a urologic and pelvic pain symptom evaluation, and those from CRD, from both a urologic and bowel symptom evaluation., Conclusions: SNM shows positive effects across various pelvic floor domains, even beyond the primary intended indication of implantation. The rather rigid approach of patient selection of discipline-specific symptoms alone can be questioned. A more comprehensive evaluation encompassing various pelvic floor symptoms with the emphasis on subjective outcome measures could enhance SNM's efficacy assessment during the test phase., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT05313984., Competing Interests: Conflict of Interest Lynn Ghijselings reports a research grant from Medtronic and other from Astellas. Kim Pauwaert reports speaker fee from Coloplast, Astellas, Gedeon Richter, and Effik, outside the submitted work. François Hervé reports speaker fees from Hollister, Coloplast, Apogepha, Medtronic, and Astellas, outside the submitted work. Karel Everaert reports grants and other from Ferring, grants from Astellas, and grants and other from Medtronic, outside the submitted work. The remaining authors report no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: ST-segment elevation myocardial infarction (STEMI) is associated with a systemic and local inflammatory response with edema. However, their role at the tissue level is poorly characterized., Objectives: This study aims to characterize T2 values of the noninfarcted myocardium (NIM) and surrounding tissue and to investigate prognostic relevance of higher NIM T2 values after STEMI., Methods: A total of 171 consecutive patients with STEMI without prior cardiovascular events who underwent cardiac magnetic resonance after primary percutaneous coronary intervention were analyzed in terms of standard infarct characteristics. Edema of the NIM, liver, spleen, and pectoralis muscle was assessed based on T2 mapping. Follow-up was available for 130 patients. The primary endpoint was major adverse cardiac events (MACE), defined as cardiovascular death, myocardial infarction, unplanned coronary revascularization or rehospitalization for heart failure. The median time from primary percutaneous coronary intervention to cardiac magnetic resonance was 3 days (IQR: 2-5 days)., Results: Higher (above the median value of 45 ms) T2 values in the NIM area were associated with larger infarct size, microvascular obstruction, and left ventricular dysfunction and did not correlate with C-reactive protein, white blood cells, or T2 values of the pectoralis muscle, liver, and spleen. At a median follow-up of 17 months, patients with higher (>45 ms) NIM T2 values had increased risk of MACE (P < 0.001) compared with subjects with NIM T2 values ≤45 ms, mainly caused by a higher rate of myocardial reinfarction (26.3% vs 1.4%; P < 0.001). At multivariable analysis, higher NIM T2 values independently predicted MACE (HR: 2.824 [95% CI: 1.254-6.361]; P = 0.012)., Conclusions: Higher NIM T2 values after STEMI are independently associated with worse cardiovascular outcomes, mainly because of higher risk of myocardial infarction., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The rapid and reliable differentiation of myocardial infarction (MI) due to atherothrombosis (T1MI) from MI due to supply-demand mismatch (T2MI) or acute myocardial injury is of major clinical relevance due to very different treatments, but still a major unmet clinical need. This study aimed to investigate whether copeptin, a stress hormone produced in the hypothalamus, helps to differentiate between T1MI versus T2MI or injury., Methods: In a retrospective analysis, 1271 unselected consecutive patients presenting with symptoms suggestive of MI to the emergency department were evaluated. Patients diagnosed with ST-elevation MI were excluded. All patients with elevated cardiac troponin I (cTnI) concentration possibly indicating MI were classified into T1MI, T2MI, or acute myocardial injury using detailed clinical assessment and coronary imaging. Copeptin plasma concentration was measured in a blinded fashion. A multicenter diagnostic study with central adjudication of the final diagnosis served as external validation cohort (n = 1390)., Results: Among 1161 patients, 154 patients had increased cTnI concentration. Of these, 78 patients (51%) were classified as T1MI and 76 (49%) as T2MI or myocardial injury. Patients with T2MI or myocardial injury had significantly higher copeptin plasma concentration between patients versus T1MI (21,4 pmol/l versus 8,1 pmol/l, p = 0,001). A multivariable regression analysis revealed that higher concentrations of copeptin and C-reactive protein, higher heart rate at presentation and lower frequency of smoking remained significantly associated with T2MI and myocardial injury. Findings were largely confirmed in the external validation cohort., Conclusion: In patients without ST-segment elevation, copeptin concentration was higher in T2MI and myocardial Injury versus T1MI and may help in their differential diagnosis., Competing Interests: Declaration of competing interest Dr. Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the University of Basel, the University Hospital Basel, Abbott, Astra Zeneca, Beckman Coulter, Brahms, Idorsia, LSI-Medience, Novartis, Ortho Clinical Diagnostics, Quidel, Roche, Siemens, Singulex, Sphingotec, as well as speaker honoraria/consulting honoraria from Amgen, Astra Zeneca, Bayer, Beckman Coulter, Boehringer Ingelheim, BMS, Idorsia, Novartis, Osler, Roche, Sanofi, Siemens, and Singulex. Dr. Huber has received speaker honoraria/consulting honoraria from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, Chiesi, Daiichi Sankyo, Ferrer, Novartis, NovoNordisk, and Sanofi Aventis. All other authors have no COIs. This study received no grant support. No conflicts of interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Contrast media (CM)-associated adverse effects including mainly acute kidney injury and hypersensitivity reactions still remain a significant treatment burden to vulnerable patients requiring percutaneous coronary intervention (PCI). The complete omission of CM administration accompanied by intravascular ultrasound (IVUS) guidance may offer an appropriate revascularization treatment., Methods: We hereby present a case series of four patients with challenging coronary lesions and relative/absolute contraindications to CM use [(hypersensitivity reaction owning to CM, history of contrast-induced acute kidney injury, solitary kidney, or advanced chronic kidney disease (CKD)] who underwent absolute zero-contrast IVUS-guided PCI following a predetermined protocol., Results: The initial diagnostic angiography was reviewed for landmark identification, and multiple guidewires created a metallic road map providing additional landmarks and protected side branches. IVUS imaging was performed to determine lesion length, reference segments and landing zones, assess stent expansion/apposition and identify major complications. All procedures were successfully completed without any CM administration, renal function deterioration, pericardial effusion, or stent edge dissection., Conclusions: We demonstrated the feasibility of absolute zero-contrast IVUS-guided PCI in patients with complex coronary lesions susceptible to CM-associated adverse effects. Since the safety of this strategy is well-documented in patients with CKD and challenging lesions morphology even in acute settings, evidence-based validation of this approach is capable of changing the otherwise conservative treatment of vulnerable patients where even minimum doses of CM may have detrimental effects., Summary for the Annotated Table of Contents: Patients with vulnerable renal function as well as former hypersensitivity reaction to contrast media encounter a significant treatment burden regarding coronary artery disease. Zero-contrast IVUS-guided strategy based on a predetermined protocol provides a feasible alternative approach in patients susceptible to contrast media-associated adverse effects even in the presence of complex coronary lesions., Competing Interests: Declaration of competing interest Dimitri Karmpaliotis reports honoraria support provided by Boston Scientific and Abbott Vascular and equity in Saranas, Traverse Vascular, Soundbite and Nanowear. No potential competing interest was reported by Xenofon M Sakellariou, Michail I Papafaklis, Christos Floros, Lampros K Michalis and Christos S Katsouras., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 μmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Electromyographic evaluation is a reliable tool for confirming facial palsy and assessing its severity. It allows differentiating facial paresis and paralysis, and further distinguishes acute palsies, still showing muscle fibrillations, from chronic cases. This article aims to show that EMG fibrillations might represent a better criterion to differentiate acute and chronic palsies than the standard 18-24 months' cut-off usually employed for classification and treatment purposes. We performed a cohort study using the eFACE tool for comparing triple innervation facial reanimation results in patients with EMG fibrillation treated <12 months, 12-18 months, and >18 months from paralysis onset. Patients showed a statistically significant post-operative improvement in all eFACE items, both in the whole sample and in the three groups. Only the deviation from the optimal score for the gentle eye closure item in group 2 didn't reach statistical significance (p = 0.173). The post-operative results were comparable in the three groups, as the Kruskal-Wallis test showed a difference only for the platysmal synkinesis item scores, which were significantly lower in group 3 (p = 0.025)., (Copyright © 2024 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Introduction: Autologous fat transfer (AFT) is widely used to improve results of breast reconstructive surgery, but its safety is controversial. Our objective was to evaluate the oncologic safety of AFT in a homogeneous population of patients who underwent a total mastectomy with immediate reconstruction for breast cancer., Methods: We performed a retrospective cohort study by identifying all patients who underwent immediate breast reconstruction after mastectomy for breast cancer from 2007 to 2015 in our center. A patient group with AFT performed in the 24 months after mastectomy was compared to a control group., Results: Five hundred fifty cases were included, of whom 136 (24.7%) underwent at least one fat graft transfer. Median age was 51 years. Reconstruction was performed in 465 (84.5%) with an implant reconstruction. The median time from mastectomy to AFT was 13.8 months. The median follow up was 55.2 months. A total of 53 events were observed, including 10 (7.4%) in the AFT group and 43 (10.4%) in the control group. There was no difference in 5-year recurrence-free survival (RFS) between the groups. In the subgroup analysis, only lymph node involvement in patients who underwent AFT in the first 24 months after oncologic surgery appeared as a risk factor of recurrence. Among the 104 patients with lymph node involvement, 5-year RFS was 69.2% in patients with lipofilling vs 92.5% in patients without it (p = 0 0.0351)., Conclusion: Performing early lipofilling in primary breast reconstruction after mastectomy for cancer seems to be oncologically safe. Lymph node involvement increases the risk of recurrence in this population., 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., (© 2024 Published by Elsevier Ltd.)

Objectives: To determine the 12-month cumulative incidence, characteristics, and associated factors of pressure injuries acquired in Intensive Care Units., Setting: Four intensive care units in a Norwegian University Hospital., Research Methodology: A prospective observational cohort study using data from daily skin inspections during a quality improvement project. We used descriptive statistics and logistic regression. Variables associated with the development of intensive care unit-acquired pressure injuries are presented with odds ratios (OR), and 95% confidence intervals., Results: The 12-month cumulative incidence of patients (N = 594) developing intensive care unit-acquired pressure injuries was 29 % (172/594) for all categories and 16 % (95/594) when excluding category I pressure injuries (no skin loss). Cumulative incidence for patients acquiring medical device-related pressure injuries was 15 % (91/594) and 11 % (64/594) for category II or worse. Compression stockings (n = 51) and nasogastric tubes (n = 22) were the most frequent documented medical devices related to pressure injuries. Development of pressure injuries category II or worse was significantly associated with vasoactive drug infusions (OR 11.84, 95 % CI [1.59; 88.13]) and longer intensive care unit length of stay (OR 1.06, 95 % CI [1.04; 1.08])., Conclusion: The 12-month cumulative incidence of intensive care unit-acquired pressure injuries was relatively high when category I pressure injuries were included, but comparable to other studies when category I was excluded. Some medical device-related pressure injuries were surprisingly frequent, and these may be prevented. However, associated factors of developing pressure injuries were present and deemed non-modifiable., Implications for Clinical Practice: Awareness about pressure injury prevention is needed in the intensive care unit considering high incidences. Nurses can detect category I pressure injuries early, which may be reversed. Our findings show several factors that clinicians can control to reduce the risk of pressure injuries in the intensive care unit., 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 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Multivalvular heart disease (MVHD) is present in one-third of patients with valvular heart disease (VHD). Compared to single VHD patients, these patients have a more significant hemodynamic impact and are often left under medical treatment. Most importantly, when undergoing multiple valve interventions, they show worse rates of heart failure and mortality. The guidelines-supported interventions in patients with MVHD in combined aortic regurgitation and mitral stenosis include percutaneous mitral balloon commissurotomy, open mitral commissurotomy, or surgical mitral valve replacement followed by transcatheter or surgical aortic valve replacement, trying to minimize the increased mortality risk of double-valve replacement. Simultaneous transcatheter valve replacement (STVR) for native MVHD is still off-label and not yet considered in clinical guidelines since the evidence of its results is limited to a few cases reported worldwide. However, fully percutaneous transfemoral STVR seems promising for MVHD patients thanks to its minimal invasiveness, the continuous improvement of the transcatheter heart valve devices, the likely shorter length of stay and the fastest recovery. To our knowledge, this is the first case ever reported of fully percutaneous STVR for native MVHD in aortic regurgitation and mitral stenosis. Deep understanding of both pathologies and their interactions, not only from a pathological point of view but from the procedural planning and procedural steps point of view is mandatory. Hereby we present the specific STVR procedural planning considerations, a step-by-step guide on how to perform an aortic and mitral STVR and its critical considerations, as well as the procedural and follow-up results., Competing Interests: The authors report no conflict of interest., (© 2024 The Author(s).)

Traumatic subarachnoid hemorrhage (tSAH) is frequently comorbid with traumatic brain injury (TBI) and may induce secondary injury through vascular changes such as vasospasm and subsequent delayed cerebral ischemia (DCI). While aneurysmal SAH is well studied regarding vasospasm and DCI, less is known regarding tSAH and the prevalence of vasospasm and DCI, the consequences of vasospasm in this setting, when treatment is indicated, and which management strategies should be implemented. In this article, a systematic review of the literature that was conducted for cases of symptomatic vasospasm in patients with TBI is reported, association with tSAH is reported, risk factors for vasospasm and DCI are summarized, and commonalities in diagnosis and management are discussed. Clinical characteristics and treatment outcomes of 38 cases across 20 studies were identified in which patients with TBI with vasospasm underwent medical or endovascular management. Of the patients with data available for each category, the average age was 48.7 ± 20.3 years (n = 31), the Glasgow Coma Scale score at presentation was 10.6 ± 4.5 (n = 35), and 100% had tSAH (n = 29). Symptomatic vasospasm indicative of DCI was diagnosed on average at postinjury day 8.4 ± 3.0 days (n = 30). Of the patients, 56.6% (n = 30) had a new ischemic change associated with vasospasm confirming DCI. Treatment strategies are discussed, with 11 of 12 endovascularly treated and 19 of 26 medically treated patients surviving to discharge. tSAH is associated with vasospasm and DCI in moderate and severe TBI, and patients with clinical and radiographic evidence of symptomatic vasospasm and subsequent DCI may benefit from endovascular or medical management strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Intravascular ultrasound (IVUS) studies show that one-quarter of left anterior descending (LAD) arteries have a myocardial bridge. An MB may be associated with stent failure when the stent extends into the MB., Objectives: The aim of this study was to investigate: 1) the association between an MB and chronic total occlusion (CTO) in any LAD lesions; and 2) the association between an MB and subsequent clinical outcomes after percutaneous coronary intervention in LAD CTOs., Methods: A total of 3,342 LAD lesions with IVUS-guided percutaneous coronary intervention (280 CTO and 3,062 non-CTO lesions) were included. The primary outcome was target lesion failure (cardiac death, target vessel myocardial infarction, definite stent thrombosis, and ischemic-driven target lesion revascularization)., Results: An MB by IVUS was significantly more prevalent in LAD CTOs than LAD non-CTOs (40.4% [113/280] vs 25.8% [789/3,062]; P < 0.0001). The discrepancy in CTO length between angiography and IVUS was greater in 113 LAD CTOs with an MB than 167 LAD CTOs without an MB (6.0 [Q1, Q3: 0.1, 12.2] mm vs 0.2 [Q1, Q3: -1.4, 8.4] mm; P < 0.0001). Overall, 48.7% (55/113) of LAD CTOs had a stent that extended into an MB after which target lesion failure was significantly higher compared to a stent that did not extend into an MB (26.3% vs 0%; P = 0.0004) or compared to an LAD CTO without an MB (26.3% vs 9.6%; P = 0.02)., Conclusions: An MB was more common in LAD CTO than non-CTO LAD lesions. If present, approximately one-half of LAD CTOs had a stent extending into an MB that, in turn, was associated with worse outcomes., Competing Interests: Funding Support and Author Disclosures Dr Karmpaliotis has received honoraria from Boston Scientific and Abbot Vascular; and holds equity in Saranas Soundbite and Traverse Vascular. Dr Matsumura is a consultant for Terumo Corporation and Boston Scientific. Dr Fall is a consultant for INFRAREDX and Boston Scientific. Dr Prasad is a consultant for CONAVI, Neovasc, Abbott Vascular, Cardinol, Chiesi, and Boehringer Ingelheim; and is on the Speakers Bureau for CONAVI, Neovasc, Abbott Vascular, Cardinol, Chiesi, and Boehringer Ingelheim. Dr Ng has received honoraria from Edwards Lifesciences and Medtronic. Dr Parikh has received research grants from Abbott, Boston Scientific, Medtronic, Phillips, Cordis, Jannsen; is a consultant for Inari, Penumbra, Terumo, and Canon; and holds equity in eFemoral, Advanced Nano Therapies, and Encompass Vascular. Dr Ali has received grants from Abbott Vascular and CSI; is a consultant for Amgen, AstraZeneca, and Boston Scientific; and holds equity for Shockwave. Dr Leon has received institutional clinical research grants from Abbott Vascular, Boston Scientific, and Medtronic. Dr McEntegart has received honoraria from Boston Scientific, Abbot Vascular, Shockwave Medical, Teleflex, and Biosensors. Dr Moses holds equity in Orchestra Biomed and Xenter. Dr Kirtane has received institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, Siemens, Philips, ReCor Medical, and Neurotronic; has received institutional funding including fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which Dr Kirtane controlled the content; is a consultant for IMDS; and has received travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr Ochiai has received consulting fees from Abbott, Asahi Intecc, Boston Scientific, and Terumo. Dr Mintz has received honoraria from Boston Scientific, Philips, SpectraWave, and Gentuity. Dr Maehara has received research grants from Boston Scientific and Abbott Vascular; and is a consultant for Boston Scientific and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Capturing the breadth of chemical exposures in utero is critical in understanding their long-term health effects for mother and child. We explored methodological adaptations in a Non-Targeted Analysis (NTA) pipeline and evaluated the effects on chemical annotation and discovery for maternal and infant exposure. We focus on lesser-known/underreported chemicals in maternal and umbilical cord serum analyzed with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). The samples were collected from a demographically diverse cohort of 296 maternal-cord pairs (n = 592) recruited in San Francisco Bay area. We developed and evaluated two data processing pipelines, primarily differing by detection frequency cut-off, to extract chemical features from non-targeted analysis (NTA). We annotated the detected chemical features by matching with EPA CompTox Chemicals Dashboard (n = 860,000 chemicals) and Human Metabolome Database (n = 3140 chemicals) and applied a Kendrick Mass Defect filter to detect homologous series. We collected fragmentation spectra (MS/MS) on a subset of serum samples and matched to an experimental MS/MS database within the MS-Dial website and other experimental MS/MS spectra collected from standards in our lab. We annotated ~72 % of the features (total features = 32,197, levels 1-4). We confirmed 22 compounds with analytical standards, tentatively identified 88 compounds with MS/MS spectra, and annotated 4862 exogenous chemicals with an in-house developed annotation algorithm. We detected 36 chemicals that appear to not have been previously reported in human blood and 9 chemicals that were reported in less than five studies. Our findings underline the importance of NTA in the discovery of lesser-known/unreported chemicals important to characterize human exposures., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Nutritional status is paramount in Cystic Fibrosis (CF) and is directly correlated with morbidity and mortality. The first ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with CF were published in 2016. An update to these guidelines is presented., Methods: The study was developed by an international multidisciplinary working group in accordance with officially accepted standards. Literature since 2016 was reviewed, PICO questions were discussed and the GRADE system was utilized. Statements were discussed and submitted for on-line voting by the Working Group and by all ESPEN members., Results: The Working Group updated the nutritional guidelines including assessment and management at all ages. Supplementation of vitamins and pancreatic enzymes remains largely the same. There are expanded chapters on pregnancy, CF-related liver disease, and CF-related diabetes, bone disease, nutritional and mineral supplements, and probiotics. There are new chapters on nutrition with highly effective modulator therapies and nutrition after organ transplantation., Competing Interests: Conflict of interest The expert members of the working group were accredited by the ESPEN Guidelines Group, the ESPEN Education and Clinical Practice Committee, and the ESPEN executive. All expert members have declared their individual conflicts of interest according to the rules of the International Committee of Medical Journal Editors (ICMJE). If potential conflicts were indicated, they were reviewed by the ESPEN guideline officers and, in cases of doubts, by the ESPEN executive. None of the expert panel had to be excluded from the working group or from co-authorship because of serious conflicts. The conflict of interest forms are stored at the ESPEN guideline office and can be reviewed with legitimate interest upon request to the ESPEN executive., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The Camargue or Rhône delta is a coastal wetland in southern France of which parts formerly devoted to salt production are undergoing a renaturation process. This study assessed a multisensor approach to investigate the link between sediment size distribution, habitat development mapped with Worldview 2, flooding durations estimated with time series of SENTINEL 2 images and elevation modelled with a LIDAR point cloud in former saltworks. A Random Forest classification algorithm was used to map the vegetation distributions of Sarcocornia fruticosa and Arthrocnemum macrostachyum, main representatives of the NATURA 2000 "Mediterranean and thermo-Atlantic halophilous scrubs (Sarcocornetea fruticosi)" habitat on the site. The best habitat map was obtained when considering the species separately. The random forest Out-of-bag errors were 1.43 % for S. fruticosa and 2.18 % for A. macrostachyum. Both species were generally distributed on different elevation and flooding duration zones considering mean values. Flooding duration was estimated with the Water In Wetland index (WIW) based on 15 Sentinel-2 scenes. Two models related to sediment grain size distribution were developed: one predicting the flooding duration and one predicting the halophilous scrub distribution. Maps of flooding duration, sediment grain size distribution and elevation highlighted two main zones in the study area: a western section with coarser sediments, shorter flooding durations and higher elevations under sea influence; an eastern section with finer sediments, longer hydroperiods and lower elevations under a historic river influence. This multidisciplinary approach offers perspectives for using space-based data over large scales to monitor changes in edaphic conditions of coastal areas facing natural and anthropogenic forcings. The results call for further investigations to predict the dynamic distribution of other coastal habitats following climate change impacts, such as sea level rise., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Due to climate change, decreasing ice cover and increasing industrial activities, Arctic marine ecosystems are expected to face higher levels of anthropogenic stress. To sustain healthy and productive ocean ecosystems, it is imperative to build baseline data to assess future climatic and environmental changes. Herein, a natural oil seep site offshore western Svalbard (Prins Karls Forland, PKF, 80-100 m water depth), discovered using satellite radar images, was investigated using an extensive multiscale and multisource geospatial dataset collected by satellite, aerial, floating, and underwater platforms. The investigated PKF seep area covers roughly a seafloor area of 30,000 m 2 and discharges oil from Tertiary or younger source rocks. Biomarker analyses confirm that the oil in the slicks on the sea surface and from the seep on the seafloor have the same origin. Uranium/Thorium dating of authigenic carbonate crusts indicated that the seep had emanated since the Late Pleistocene when ice sheet melting unlocked the hydrocarbons trapped beneath the ice. The faunal communities at the PKF seep are a mix of typical high latitude fauna and taxa adapted to reducing environments. Remarkably, the inhospitable oil-impregnated sediments were also colonized by abundant infaunal organisms. Altogether, in situ observations obtained at the site provide essential insights into the characteristics of high-latitude oil seeps and can be used as a natural laboratory for understanding the potential impacts of human oil discharge into the ocean., Competing Interests: Declaration of competing interest All authors declare they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy., Competing Interests: Declaration of competing interest KWS has no competing interests. See supplementary materials for full CoI statements for all authors., (Copyright © 2023. Published by Elsevier B.V.)

Advanced age is the most important risk factor for Alzheimer's disease (AD), and carrier-status of the Apolipoprotein E4 (APOE4) allele is the strongest known genetic risk factor. Many studies have consistently shown a link between APOE4 and synaptic dysfunction, possibly reflecting pathologically accelerated biological aging in persons at risk for AD. To test the hypothesis that distinct functional connectivity patterns characterize APOE4 carriers across the clinical spectrum of AD, we investigated 128 resting state functional Magnetic Resonance Imaging (fMRI) datasets from the Alzheimer's Disease Neuroimaging Initiative database (ADNI), representing all disease stages from cognitive normal to clinical dementia. Brain region centralities within functional networks, computed as eigenvector centrality, were tested for multivariate associations with chronological age, APOE4 carrier status and clinical stage (as well as their interactions) by partial least square analysis (PLSC). By PLSC analysis two distinct brain activity patterns could be identified, which reflected interactive effects of age, APOE4 and clinical disease stage. A first component including sensorimotor regions and parietal regions correlated with age and AD clinical stage (p < 0.001). A second component focused on medial-frontal regions and was specifically related to the interaction between age and APOE4 (p = 0.032). Our findings are consistent with earlier reports on altered network connectivity in APOE4 carriers. Results of our study highlight promise of graph-theory based network centrality to identify brain connectivity linked to genetic risk, clinical stage and age. Our data suggest the existence of brain network activity patterns that characterize APOE4 carriers across clinical stages of AD., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Histologic subtype of cancer guides treatment sequencing and the extent of surgery for retroperitoneal tumours (RPTs) but concerns persist regarding percutaneous core needle biopsy (CNB)., Objective: Endpoints were the incidence of early complications, needle tract seeding (NTS) after CNB, diagnostic accuracy., Methods: Between 2015 and 2022, data from patients with RPT who underwent a CNB and who operated on at Institut Curie were collected. We retrospectively reviewed the medical records and microscopic analysis of both CNB and surgical specimens to evaluate the diagnostic accuracy of CNB (quantified using positive and negative predictive values, PPV/NPV)., Results: 313 patients underwent CNB. In 10/326 (3 %) procedures, minor complications were observed. One of 212 (0.47 %) resected RPSs exhibited a local recurrence compatible with NTS. Microscopic analysis of CNB specimens allowed the classification of tumours between groups of cancers and benign/intermediate mesenchymal tumours in 307/313 (98 %) patients. Among the 204 patients with retroperitoneal sarcoma, the overall concordance between CNB and final pathology following resection was 178/204 (87.2 %). The respective PPVs of solitary fibrous tumour, dedifferentiated liposarcoma, leiomyosarcoma and well-differentiated liposarcoma were 100 %, 98 %, 97 % and 68 %, respectively. The diagnosis of a high-grade (G 2-3) sarcoma resulted in a high specificity (97 %) and PPV (98 %) but low sensitivity (76 %)., Conclusions: CNB allowed the classification of RPT in the vast majority of patients with a low morbidity rate. Concordance with final diagnosis was high for sarcomas with the exception of well-differentiated liposarcoma. As a result, CNB results should be integrated with imaging/radiomics by multidisciplinary tumour boards., Competing Interests: Declaration of competing interest Tha authors have no conflict of interest to declare. No Funder, no grant for this work, (© 2023 Published by Elsevier Ltd.)

In recent years, transformation products-(TPs) of pharmaceuticals in the environment have received considerable attention. In this context, here, a customized overview of transformation of Furosemide-(FRS) in aqueous matrices treated by photo-oxidation is provided as a proof of concept. Hence, the primary goal of the study was to display an integrated strategy by combining the target (parent-molecule) and suspect screening-(SS) approaches (TPs) in order to build an in-house High-Resolution mass spectrometry (HRMS) database able to provide reference information (chromatographic/spectral) for environmental investigations in complex matrices (wastewaters/landfill leachates). Data analysis was performed by optimizing a SS workflow. Additional confirmation for the proposed structural elucidation was provided by correlating retention time to the proposed structure employing three prediction models. This approach was applied for the tentative identification of 35 TPs of FRS, 28 of which are reported herein for the first time. Finally, SS and non-target analysis (NTA) have been successfully applied for retrospective screening of FRS and its TPs in real samples. The findings demonstrated that SS allows the proper identification of TPs of FRS in complex matrices proving its outstanding importance compared to NTA. In total, six TPs were identified by SS with potential ecotoxicological implications for two of them according to in silico risk assessment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D. A. Lambropoulou reports financial support was provided by European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship, and Innovation under the call RESEARCH - CREATE - INNOVATE (2nd Cycle)., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The analysis of the brain extracellular metabolome is of interest for numerous subdomains within neuroscience. Not only does it provide information about normal physiological functions, it is even more of interest for biomarker discovery and target discovery in disease. The extracellular analysis of the brain is particularly interesting as it provides information about the release of mediators in the brain extracellular fluid to look at cellular signaling and metabolic pathways through the release, diffusion and re-uptake of neurochemicals. In vivo samples are obtained through microdialysis, cerebral open-flow microperfusion or solid-phase microextraction. The analytes of potential interest are typically low in concentration and can have a wide range of physicochemical properties. Liquid chromatography coupled to mass spectrometry has proven its usefulness in brain metabolomics. It allows sensitive and specific analysis of low sample volumes, obtained through different approaches. Several strategies for the analysis of the extracellular fluid have been proposed. The most widely used approaches apply sample derivatization, specific stationary phases and/or hydrophilic interaction liquid chromatography. Miniaturization of these methods allows an even higher sensitivity. The development of chiral metabolomics is indispensable, as it allows to compare the enantiomeric ratio of compounds and provides even more challenges. Some limitations continue to exist for the previously developed methods and the development of new, more sensitive methods remains needed. This review provides an overview of the methods developed for sampling and liquid chromatography-mass spectrometry analysis of the extracellular metabolome., 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.)

Introduction: The Emerging Drugs Network of Australia - Victoria (EDNAV) project is a newly established toxicosurveillance network that collates clinical and toxicological data from patients presenting to emergency departments with illicit drug related toxicity in a centralised clinical registry. Data are obtained from a network of sixteen public hospital emergency departments across Victoria, Australia (13 metropolitan and three regional). Comprehensive toxicological analysis of a purposive sample of 22 patients is conducted each week, with reporting of results to key alcohol and other drug stakeholders. This paper describes the overarching framework and risk-based approach developed within Victoria to assess drug intelligence from EDNAV toxicosurveillance., Methods: Risk management principles from other spheres of public health surveillance and healthcare clinical governance have been adapted to the EDNAV framework with the aim of facilitating a consistent and evidence-based approach to assessing weekly drug intelligence. The EDNAV Risk Register was reviewed over the first two years of EDNAV project operation (September 2020 - August 2022), with examples of eight risk assessments detailed to demonstrate the process from signal detection to public health intervention., Results: A total of 1112 patient presentations were documented in the EDNAV Clinical Registry, with 95 signals of concern entered into the EDNAV Risk Register over the two-year study period. The eight examples examined in further detail included suspected drug adulteration (novel opioid adulterated heroin, para-methoxymethamphetamine adulterated 3,4-methylenedioxymethamphetamine (MDMA)), drug substitution (25B-NBOH sold as lysergic acid diethylamide, five benzodiazepine-type new psychoactive substances in a single tablet, protonitazene sold as ketamine), new drug detection (N,N-dimethylpentylone), contamination (unreported acetylfentanyl) and a fatality subsequent to MDMA use. A total of four public Drug Alerts were issued over this period., Conclusions: Continued toxicosurveillance efforts are paramount to characterising the changing landscape of illicit drug use. This work demonstrates a functional model for risk assessment of illicit drug toxicosurveillance, underpinned by analytical confirmation and evidence-based decision-making., 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. Published by Elsevier B.V.)

Introduction: The emergence of benzodiazepine-type new psychoactive substances (NPSs) are a growing international public health concern, with increasing detections in drug seizures and clinical and coronial casework. This study describes the patterns and nature of benzodiazepine-type NPS detections extracted from the Emerging Drugs Network of Australia - Victoria (EDNAV) project, to better characterise benzodiazepine-type NPS exposures within an Australian context., Methods: EDNAV is a state-wide illicit drug toxicosurveillance project collecting data from patients presenting to an emergency department with illicit drug-related toxicity. Patient blood samples were screened for illicit, pharmaceutical and NPSs utilising liquid chromatography-tandem mass spectrometry. Demographic, clinical, and analytical data was extracted from the centralised registry for cases with an analytical confirmation of a benzodiazepine-type NPS(s) between September 2020-August 2022., Results: A benzodiazepine-type NPS was detected in 16.5 % of the EDNAV cohort (n = 183/1112). Benzodiazepine-type NPS positive patients were predominately male (69.4 %, n = 127), with a median age of 24 (range 16-68) years. Twelve different benzodiazepine-type NPSs were detected over the two-year period, most commonly clonazolam (n = 82, 44.8 %), etizolam (n = 62, 33.9 %), clobromazolam (n = 43, 23.5 %), flualprazolam (n = 42, 23.0 %), and phenazepam (n = 31, 16.9 %). Two or more benzodiazepine-type NPSs were detected in 47.0 % of benzodiazepine-type NPS positive patients. No patient referenced the use of a benzodiazepine-type NPS by name or reported the possibility of heterogenous product content., Conclusion: Non-prescription benzodiazepine use may be an emerging concern in Australia, particularly amongst young males. The large variety of benzodiazepine-type NPS combinations suggest that consumers may not be aware of product heterogeneity upon purchase or use. Continued monitoring efforts are paramount to inform harm reduction opportunities., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shaun L. Greene reports financial support was provided by Victoria Department of Health. Shaun L. Greene reports financial support was provided by National Health and Medical Research Council., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)