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The mineralogy of niobium (Nb) is characterized by multicomponent oxides such as AB2O6, A2B2O7, ABO4, and ABO3 in which Nb is incorporated in the B site. Such complex crystal-chemistry prevents their unambiguous identification in ore deposits such as hydrothermal rocks and laterites which exhibit complex and fine-grained textures. The understanding of the processes controlling Nb ore deposit formation in various geological settings is therefore limited, although Nb is a critical element. In this study, we use X-ray absorption spectroscopy (XAS) at the Nb K-edge to investigate the local atomic-scale structure around Nb in a large set of natural and synthetic minerals of geological and technological importance. Our X-ray absorption near-edge structure (XANES) data at the Nb K-edge show three major features of variable position and intensity and then can be related to the local distortion and coordination number of the Nb site. Shell-by-shell fits of the extended X-ray absorption fine structure (EXAFS) data reveal that the NbO6 octahedra are distorted in a variety of pyrochlore species. At least two distinct first shells of O atoms are present while reported crystallographic data yield regular octahedra in the same minerals. Next-nearest Nb–Nb distances in pyrochlore and Nb-bearing perovskite mirror a corner-sharing NbO6 network, whereas the two Nb–Nb distances in columbite are typical of edge- and corner-sharing NbO6 octahedra. Such a resolution on the Nb site geometry and the intersite relationships between the next-nearest NbO6 octahedra is made possible by collecting EXAFS data under optimal conditions at 20 K and up to 16 Å−1. The local structure around substituted Nb5+ in Fe3+, Ti4+, and Ce4+ oxides suffers major changes relative to the unsubstituted structures. The substitution of Nb5+ for Ti4+ in anatase leads to the increase in the interatomic distances between Nb and its first and second Ti4+ neighbors. The substitution of Nb5+ for Ce4+ in cerianite reduces the coordination number of the cation from eight to four, and the Nb–O bonds are shortened compared to Ce–O ones. In hematite, Nb5+ occupies a regular site, whereas the Fe3+ site is strongly distorted suggesting major site relaxation due to charge mismatch. The sensitivity of XANES and EXAFS spectroscopies at the Nb K-edge to the local site geometry and next-nearest neighbors demonstrated in this study would help decipher Nb speciation and investigate mineralogical reactions of Nb minerals in deposit-related contexts such as hydrothermal and lateritic deposits.

Evolution of organic carbon content in soils has the potential to be a major driver of atmospheric greenhouse gas concentrations over the next century. Understanding soil carbon dynamics is a challenge due to a wide range of residence times of soil organic matter and limited constraints on the mechanisms influencing its persistence. In particular, large uncertainties exist regarding the persistence of pyrogenic organic carbon in soils. In order to characterize organic matter with varying degrees of persistence and to distinguish pyrogenic organic carbon, we combined Rock-Eval analysis, a thermo-chemical method, with the benzene polycarboxylic acid molecular marker method and Raman spectroscopy to characterize samples from long-term bare-fallow experiments, progressively depleted in the most labile organic carbon over time. Considering the heterogeneity of soil samples, size fractions have been separated to distinguish pools of organic carbon with distinct properties. We observe that organic carbon dynamics is dependent on granulometry. A pool of organic carbon with intermediate residence times, from years to a few decades, representing ca. 65 % of the bulk soil organic carbon stock, is mainly associated with fine fractions (< 20 µm). With time under bare fallow, this organic carbon is progressively transferred towards finer fractions through the breakdown of organic matter. Coarse fractions (> 20 µm) are rich in centennially persistent organic carbon, representing ca. 20 % of the initial organic carbon stock, due to the chemical recalcitrance of organic matter in these fractions, dominated by pyrogenic organic carbon. A second pool of persistent organic carbon, representing ca. 15 % of the initial organic carbon stock, is associated with the clay fraction, indicating mechanisms of protection occurring at the submicron scale (< 2 µm). This persistent organic carbon only represents 30 % of the organic carbon initially present in the clay fraction. Persistent organic carbon exhibits heterogeneous chemical signatures depending on the considered pool but a consistent thermal signature demonstrating the relationship between thermal stability and biogeochemical stability of soil organic carbon. This gives the possibility of assessing the size of the persistent organic carbon pool in soils using thermal parameters. The persistence of pyrogenic organic carbon in the clay fraction is similar to the one of total organic carbon. The different persistence of coarse and fine pyrogenic organic carbon resides in the highly condensed nature of sand-sized pyrogenic carbon, which may result from burning temperatures over 700 ∘C. Pyrogenic organic carbon is not inert but exhibits a consistent increase in the level of condensation with time in all size fractions, showing the role of chemical quality in pyrogenic organic carbon persistence. Overall, this study helps improve the separation, evaluation and characterization of carbon pools with distinct residence times in soils and gives insight into the mechanistic origin of soil organic carbon dynamics.

Abstract Background Conducting prospective epidemiological studies of hospitalized patients with rare diseases like primary subarachnoid hemorrhage (pSAH) are difficult due to time and budgetary constraints. Routinely collected administrative data could remove these barriers. We derived and validated 3 algorithms to identify hospitalized patients with a high probability of pSAH using administrative data. We aim to externally validate their performance in four hospitals across Canada. Methods Eligible patients include those ≥18 years of age admitted to these centres from January 1, 2012 to December 31, 2013. We will include patients whose discharge abstracts contain predictive variables identified in the models (ICD-10-CA diagnostic codes I60** (subarachnoid hemorrhage), I61** (intracranial hemorrhage), 162** (other nontrauma intracranial hemorrhage), I67** (other cerebrovascular disease), S06** (intracranial injury), G97 (other postprocedural nervous system disorder) and CCI procedural codes 1JW51 (occlusion of intracranial vessels), 1JE51 (carotid artery inclusion), 3JW10 (intracranial vessel imaging), 3FY20 (CT scan (soft tissue of neck)), and 3OT20 (CT scan (abdominal cavity)). The algorithms will be applied to each patient and the diagnosis confirmed via chart review. We will assess each model’s sensitivity, specificity, negative and positive predictive value across the sites. Discussion Validating the Ottawa SAH Prediction Algorithms will provide a way to accurately identify large SAH cohorts, thereby furthering research and altering care.

Grape and apple skins and seeds are rich in natural antioxidant compounds known as polyphenols. Polyphenols exhibit a wide range of beneficial biological properties acting as antioxidants and anti- inflammatory that can be exploited for vascular diseases. The polyphenol content in grapes and apples depends on cultivar and growing conditions. For this study, four different cultivars of apples (Golden Delicious, Jonagold, Renetta Canada and Raventze) and three of grapes (Fumin, Premetta and Petit Rouge), typical of Aosta Valley (Italy), were harvested at commercial maturity. Skins were collected and dried. Powdered samples were extracted with methanol using microwave assisted extraction (MAE, 110 °C, 60 min) and high pressure and temperature extraction (HPTE, 150 °C, 150 min). The non-conventional methodologies were compared with the classic solid-liquid extraction (25 °C, 19 h). The extracts were characterized in terms of total polyphenols (TP) content and their antiradical power. HPLC analysis was also performed to quantify main single phenolic compounds. For grape and apple skins, the higher TP yields were obtained by HPTE using Jonagold and Premetta cultivars, respectively. In general, extraction yields of HPTE have reached values higher than 30 and 10 mg of Gallic Acid Equivalent per g of Dry Material for grape and apple skins, respectively. Moreover, the biological vaso-protective activity of apple extracts was investigated by evaluating the expression of endothelial activation markers in an in vitro model of endothelial dysfunction induced by the pro-inflammatory cytokine TNFa.

Background: Blood loss and subsequent red blood cell transfusions are common in liver surgery. Hypovolaemic phlebotomy is associated with decreased red blood cell transfusion in observational studies. This trial aimed to investigate whether hypovolaemic phlebotomy is superior to usual care in reducing red blood cell transfusions in patients undergoing liver resection., Methods: PRICE-2 was a multicentre, single-blind, superiority randomised controlled trial. Patients at a higher risk of blood loss undergoing liver resection for any indication at four Canadian academic tertiary-care hospitals were randomised to receive hypovolaemic phlebotomy or usual care. Hypovolaemic phlebotomy consisted of the removal of 7-10 mL/kg of whole blood, without volume replacement, before liver transection. Patients were randomised centrally using permuted blocks of randomly variable length, stratified by centre. The randomisation sequence was computer-generated by an independent statistician. Surgeons, patients, and outcome assessors were masked to treatment allocation. The primary outcome was perioperative red blood cell transfusion to 30 days post-randomisation, analysed in all randomly assigned patients who underwent liver resection. PRICE-2 trial was registered with ClinicalTrials.gov (NCT03651154) and is completed., Findings: Between Oct 1, 2018, and Jan 13, 2023, 486 individuals were randomly assigned to receive hypovolaemic phlebotomy (n=245) or usual care (n=241). 22 individuals in the hypovolaemic phlebotomy group and 18 in the usual care group did not undergo liver resection and were thus excluded from the primary analysis population. 223 patients were included in the hypovolaemic phlebotomy group (mean age 61·4 years [SD 13·0]; 137 [61%] men) and 223 in the control group (62·1 years [12·1]; 114 [51%]). 17 (8%) of 223 patients allocated to hypovolaemic phlebotomy and 36 (16%) of 223 patients allocated to usual care had a perioperative red blood cell transfusion by 30 days (difference -8·8 percentage points [95% CI -14·8 to -2·8]; adjusted risk ratio [aRR] 0·47 [95% CI 0·27 to 0·82]). Severe complications to 30 days occurred in 37 (17%) patients allocated to hypovolaemic phlebotomy and 36 (16%) allocated to usual care (aRR 1·06 [95% CI 0·70-1·61]). Overall complications to 30 days occurred in 135 (61%) of 223 patients allocated to hypovolaemic phlebotomy and 116 (52%) of 223 patients allocated to usual care (1·08 [0·92-1·25]). There was no postoperative mortality to 90 days., Interpretation: In patients undergoing liver resection, hypovolaemic phlebotomy reduced perioperative red blood cell transfusion and improved operative conditions, with no statistically significant increase in the incidence of complications compared with usual care. Hypovolaemic phlebotomy should be considered for routine use in patients undergoing liver resection at higher risk of bleeding., Funding: Canadian Institutes of Health Research (PJT-156108)., Competing Interests: Declaration of interests This study was funded by a Project Grant from the Canadian Institutes of Health Research, applicable to all coauthors. GM has received research grants from the Canadian Blood Services. VM has received a speaker's honorarium from Eisai. PL has received a speaker's honorarium from Eisai, as well as a travel or conference support from the University of British Columbia. MS has received a speaker's honorarium and travel or conference support from Eisai, and holds leadership positions in the Canadian Transplant Society and the British Columbia Surgical Society Conference. AT has received research grants and speaker's honoraria from the Canadian Blood Services and is a member of an advisory board for GlaxoSmithKline. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating condition with high mortality and morbidity. The outcome measures used in aSAH clinical research vary making it challenging to compare and combine different studies. Additionally, there may be a mismatch between the outcomes prioritized by patients, caregivers, and health care providers and those selected by researchers. We conducted an international, online, multiple round Delphi study to develop consensus on domains (where a domain is a health concept or aspect) prioritized by key stakeholders including those with lived experience of aSAH, health care providers, and researchers, funders, or industry professionals. One hundred seventy-five people participated in the survey, 59% of whom had lived experience of aSAH. Over three rounds, 32 domains reached the consensus threshold pre-defined as 70% of participants rating the domain as being critically important. During the fourth round, participants ranked the importance of each of these 32 domains. The top ten domains ranked highest to lowest were (1) Cognition and executive function, (2) Aneurysm obliteration, (3) Cerebral infarction, (4) Functional outcomes including ability to walk, (5) Delayed cerebral ischemia, (6) The overall quality of life as reported by the SAH survivor, (7) Changes to emotions or mood (including depression), (8) The basic activities of daily living, (9) Vasospasm, and (10) ICU complications. Our findings confirm that there is a mismatch between domains prioritized by stakeholders and outcomes used in clinical research. Our future work aims to address this mismatch through the development of a core outcome set in aSAH research., Competing Interests: Declarations. Ethical Approval: Ethical approval for the survey development work was provided by the Ottawa Health Science Network Research Ethics Board (Reference 20210028-01H). The participants consented to participate upon registration using the web-based Delphi Manager and we informed participants that they could withdraw at any time. Conflict of Interest: Shane English is a recipient of the Heart and Stroke Foundation of Canada National New Investigator Award. The authors have no relevant financial or non-financial interests to disclose. The authors have no conflicts of interest to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary interests in any material discussed in this article., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Positron emission tomography (PET) is a highly sensitive, quantitative imaging technique that can track sub-nanomolar quantities of positron-emitting radionuclides throughout the body. By incorporating such radionuclides into molecules of interest, we can directly assess their pharmacokinetic and pharmacodynamic (PK/PD) characteristics in vivo without changing their physicochemical characteristics or eliciting a pharmacological response. As such, PET imaging has long been used as a tool to aid drug discovery programs from preclinical biomarker validation all the way through to clinical trials. In this perspective we discuss the use of PET radioligands in central nervous system (CNS) drug discovery and development, with a focus on recent applications in psychiatry (e.g. 5-HT 2 A, 11β-HSD1), neuro-oncology (e.g. KRAS G12C , ATM, ALK2), and neurodegeneration (e.g. amyloid beta plaques, MAPK p38), while exploring the intricacies associated with developing novel radiotracers for CNS targets. Examples highlight the preclinical and clinical uses of PET for studying biomarker function, drug candidate PK/PD, target occupancy/engagement, dosing regimen determination, clinical trial patient selection, and quantifying biomarker changes in response to treatments., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Neil Vasdev reports financial support was provided by Azrieli Foundation and the Canada Research Chairs Program. Melissa Chasse reports financial support was provided by Canadian Institutes of Health Research for a Canada Graduate Scholarships. 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The pathophysiological mechanisms of status epilepticus (SE) underlying potential brain injury remain largely unclear. This study aims to employ functional near-infrared spectroscopy (fNIRS) combined with video-electroencephalography (vEEG) to monitor brain hemodynamics continuously and non-invasively in critically ill adult patients experiencing electrographic SE. Our primary focus is to investigate neurovascular coupling and cerebrovascular changes associated with seizures, particularly during recurring and/or prolonged episodes., Methods: Eleven critically ill adult patients underwent simultaneous vEEG-fNIRS with large cortical coverage. Data from seven patients with identified electrographic SE were analyzed. The timing of recorded seizures was marked using standardized critical care EEG terminology. A general linear model was employed to extract the hemodynamic response to seizures from the fNIRS recordings. Linear mixed-effects models were utilized to correlate hemodynamic responses with seizure characteristics., Results: A total of >200 h of monitoring and >1000 seizures were recorded. In most patients, an increase in oxyhemoglobin (HbO) and a decrease in deoxyhemoglobin (HbR) were observed during shorter-duration seizures. Although a similar response could also be seen initially for longer-duration seizures, this hemodynamic change was often followed by a progressive decline in HbO concentration and an increase in HbR. At the systemic level, no significant difference in peripheral oxygenation occurred during seizures, and only small changes in mean arterial blood pressure and heart rate occurred in four and two patients, respectively., Significance: We demonstrate the feasibility of using multichannel vEEG-fNIRS to measure the hemodynamic changes associated with electrographic seizures in critically ill adult patients. Our findings suggest that disrupted neurovascular coupling is more prevalent during prolonged seizures compared to recurrent short-duration seizures. This research provides valuable insights into the dynamic interplay between neuronal activity and hemodynamics during critical care seizures., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: The effect of a liberal red-cell transfusion strategy as compared with a restrictive strategy in patients during the critical care period after an aneurysmal subarachnoid hemorrhage is unclear., Methods: We randomly assigned critically ill adults with acute aneurysmal subarachnoid hemorrhage and anemia to a liberal strategy (mandatory transfusion at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (optional transfusion at a hemoglobin level of ≤8 g per deciliter). The primary outcome was an unfavorable neurologic outcome, defined as a score of 4 or higher on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at 12 months. Secondary outcomes included 12-month functional independence as assessed with the Functional Independence Measure (FIM; scores range from 18 to 126) and quality of life as assessed with the EuroQol five-dimension, five-level (EQ-5D-5L) utility index (scores range from -0.1 to 0.95) and a visual analogue scale (VAS; scores range from 0 to 100); on each assessment, higher scores indicate better health status or quality of life., Results: A total of 742 patients underwent randomization at 23 centers. The analysis of the primary outcome at 12 months included 725 patients (97.7%). An unfavorable neurologic outcome occurred in 122 of 364 patients (33.5%) in the liberal-strategy group and in 136 of 361 patients (37.7%) in the restrictive-strategy group (risk ratio, 0.88; 95% confidence interval [CI], 0.72 to 1.09; P = 0.22). The mean (±SD) FIM score was 82.8±54.6 in the liberal-strategy group and 79.8±54.5 in the restrictive-strategy group (mean difference, 3.01; 95% CI, -5.49 to 11.51). The mean EQ-5D-5L utility index score was 0.5±0.4 in both groups (mean difference, 0.02; 95% CI, -0.04 to 0.09). The mean VAS score was 52.1±37.5 in the liberal-strategy group and 50±37.1 in the restrictive-strategy group (mean difference, 2.08; 95% CI, -3.76 to 7.93). The incidence of adverse events was similar in the two groups., Conclusions: In patients with aneurysmal subarachnoid hemorrhage and anemia, a liberal transfusion strategy did not result in a lower risk of an unfavorable neurologic outcome at 12 months than a restrictive strategy. (Funded by the Canadian Institutes of Health Research and others; SAHARA ClinicalTrials.gov number, NCT03309579.)., (Copyright © 2024 Massachusetts Medical Society.)

Importance: Lung biopsies are sometimes performed in mechanically ventilated patients with acute hypoxemic respiratory failure (AHRF) of unknown etiology to guide patient management. While surgical lung biopsies (SLB) offer high diagnostic rates, they may also cause significant complications. Transbronchial forceps lung biopsies (TBLB) are less invasive but often produce non-contributive specimens. Transbronchial lung cryobiopsies (TBLC) yield specimens of potentially better quality than TBLB, but due to their novel implementation in the intensive care unit (ICU), their accuracy and safety are still unclear., Objectives: Our main objective was to evaluate the risk of adverse events in patients with AHRF following the three biopsy techniques. Our secondary objectives were to assess the diagnostic yield and associated modifications of patient management of each technique., Design, Settings and Participants: We conducted a retrospective cohort study comparing TBLC, TBLB, and SLB in mechanically ventilated patients with AHRF., Main Outcomes and Measures: The primary outcome was the proportion of patients with at least one complication, and secondary outcomes included complication rates, diagnostic yields, treatment modifications, and mortality., Results: Of the 26 patients who underwent lung biopsies from 2018 to 2022, all TBLC and SLB patients and 60% of TBLB patients had at least one complication. TBLC patients had higher unadjusted numbers of total and severe complications, but also worse Sequential Organ Failure Assessment scores and P/F ratios. A total of 25 biopsies (25/26, 96%) provided histopathological diagnoses, 88% (22/25) of which contributed to patient management. ICU mortality was high for all modalities (63% for TBLC, 60% for TBLB and 50% for SLB)., Conclusions and Relevance: All biopsy methods had high diagnostic yields and the great majority contributed to patient management; however, complication rates were elevated. Further research is needed to determine which patients may benefit from lung biopsies and to determine the best biopsy modality., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear., Methods: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months., Results: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively., Conclusions: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.)., (Copyright © 2024 Massachusetts Medical Society.)

Introduction: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk., Methods and Analysis: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation., Ethics and Dissemination: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309)., Trial Registration Number: NCT05148715., Competing Interests: Competing interests: CL, FDA, FLam, FLau, F-MC and MC are recipients of research career awards from the Fonds de recherche du Québec-Santé. AFT is the chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. FDA, MW and PC received stipends for their role at Transplant Québec MaS holds research grants from the Canadian Institute of Health Research and the New Frontiers in Research Fund related to organ donation research and received a stipend for his role as the Regional Medical Lead (Donation) from Ontario Health (Trillium Gift of Life Network). MSe, RB, M-HM, MMa, A-JF, BB, AD, EC, SHo, LB, HT, PL, JGB, MKS, KEAB, JZ, SE, GK, AH, SHa, BR, SJWO, DT and MMe declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We aimed to implement four data partitioning strategies evaluated with four federated learning (FL) algorithms and investigate the impact of data distribution on FL model performance in detecting steatosis using B-mode US images. A private dataset (153 patients; 1530 images) and a public dataset (55 patient; 550 images) were included in this retrospective study. The datasets contained patients with metabolic dysfunction-associated fatty liver disease (MAFLD) with biopsy-proven steatosis grades and control individuals without steatosis. We employed four data partitioning strategies to simulate FL scenarios and we assessed four FL algorithms. We investigated the impact of class imbalance and the mismatch between the global and local data distributions on the learning outcome. Classification performance was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. AUCs were 0.93 (95% CI 0.92, 0.94) for source-based partitioning scenario with FedAvg, 0.90 (95% CI 0.89, 0.91) for a centralized model, and 0.83 (95% CI 0.81, 0.85) for a model trained in a single-center scenario. When data was perfectly balanced on the global level and each site had an identical data distribution, the model yielded an AUC of 0.90 (95% CI 0.88, 0.92). When each site contained data exclusively from one single class, irrespective of the global data distribution, the AUC fell in the range of 0.34-0.70. FL applied to B-mode US images provide performance comparable to a centralized model and higher than single-center scenario. Global data imbalance and local data heterogeneity influenced the learning outcome., (© 2024. The Author(s).)

We conducted a systematic review and network meta-analyses evaluating the effects of different intraoperative vasoactive drugs on acute kidney injury (AKI) and other perioperative outcomes in adult liver transplant recipients. We searched multiple electronic databases using words from the "liver transplantation" and "vasoactive drug" domains. We included all randomized controlled trials conducted in adult liver transplant recipients comparing 2 different intravenous vasoactive drugs or 1 against a standard of care that reported AKI, intraoperative blood loss, or any other postoperative outcome. We conducted 4 frequentist network meta-analyses using random effect models, based on the interventions' mechanism of action, and evaluated the quality of evidence (QoE) using Grading of Recommendations, Assessment, Development, and Evaluations recommendations. We included 9 randomized controlled trials comparing different vasopressor drugs (vasoconstrictor or inotrope), 3 comparing a somatostatin infusion (or its analogues) to a standard of care, 11 comparing different vasodilator infusions together or against a standard of care, and 2 comparing vasoconstrictor boluses at graft reperfusion. Intravenous clonidine was associated with shorter duration of mechanical ventilation, intensive care unit, and hospital length of stay (very low QoE), and some vasodilators were associated with lower creatinine level 24 h after surgery (low to very low QoE). Phenylephrine and terlipressin were associated with less intraoperative blood loss when compared with norepinephrine (low and moderate QoE). None of the vasoactive drugs improve any other postoperative outcomes, including AKI. There is still important equipoise regarding the best vasoactive drug to use in liver transplantation for most outcomes. Further studies are required to better inform clinical practice., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. This study evaluates the cost-effectiveness of convalescent plasma and its impact on quality-of-life to provide insight into its potential as an alternative treatment in resource-constrained settings., Methods: Individual patient data on health outcomes and resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer's perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L were measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of hospitalized inpatients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses costs from this population., Results: 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 in both arms (p = .85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms, respectively (p = .46). The incremental cost was $4458 and the incremental quality-adjusted life day was -0.078., Discussion: Convalescent plasma was less effective and more costly than standard care in treating hospitalized COVID-19., (© 2024 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Objectives: Distributed computations facilitate multi-institutional data analysis while avoiding the costs and complexity of data pooling. Existing approaches lack crucial features, such as built-in medical standards and terminologies, no-code data visualizations, explicit disclosure control mechanisms, and support for basic statistical computations, in addition to gradient-based optimization capabilities., Materials and Methods: We describe the development of the Collaborative Data Analysis (CODA) platform, and the design choices undertaken to address the key needs identified during our survey of stakeholders. We use a public dataset (MIMIC-IV) to demonstrate end-to-end multi-modal FL using CODA. We assessed the technical feasibility of deploying the CODA platform at 9 hospitals in Canada, describe implementation challenges, and evaluate its scalability on large patient populations., Results: The CODA platform was designed, developed, and deployed between January 2020 and January 2023. Software code, documentation, and technical documents were released under an open-source license. Multi-modal federated averaging is illustrated using the MIMIC-IV and MIMIC-CXR datasets. To date, 8 out of the 9 participating sites have successfully deployed the platform, with a total enrolment of >1M patients. Mapping data from legacy systems to FHIR was the biggest barrier to implementation., Discussion and Conclusion: The CODA platform was developed and successfully deployed in a public healthcare setting in Canada, with heterogeneous information technology systems and capabilities. Ongoing efforts will use the platform to develop and prospectively validate models for risk assessment, proactive monitoring, and resource usage. Further work will also make tools available to facilitate migration from legacy formats to FHIR and DICOM., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Positron emission tomography (PET) imaging of neurodegenerative disease has historically focused on a small number of established targets. The development of selective PET radiotracers for novel biological targets enables new ways to interrogate the neuropathology of proteinopathies and will advance our understanding of neurodegeneration. This perspective aims to highlight recent PET radiotracers developed for five emerging targets in proteinopathies (i.e., mHTT, BACE1, TDP-43, OGA, and CH24H)., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded., Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures., Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021)., Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing., Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus., Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition., Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis., Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.

Background Screening for nonalcoholic fatty liver disease (NAFLD) is suboptimal due to the subjective interpretation of US images. Purpose To evaluate the agreement and diagnostic performance of radiologists and a deep learning model in grading hepatic steatosis in NAFLD at US, with biopsy as the reference standard. Materials and Methods This retrospective study included patients with NAFLD and control patients without hepatic steatosis who underwent abdominal US and contemporaneous liver biopsy from September 2010 to October 2019. Six readers visually graded steatosis on US images twice, 2 weeks apart. Reader agreement was assessed with use of κ statistics. Three deep learning techniques applied to B-mode US images were used to classify dichotomized steatosis grades. Classification performance of human radiologists and the deep learning model for dichotomized steatosis grades (S0, S1, S2, and S3) was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. Results The study included 199 patients (mean age, 53 years ± 13 [SD]; 101 men). On the test set ( n = 52), radiologists had fair interreader agreement (0.34 [95% CI: 0.31, 0.37]) for classifying steatosis grades S0 versus S1 or higher, while AUCs were between 0.49 and 0.84 for radiologists and 0.85 (95% CI: 0.83, 0.87) for the deep learning model. For S0 or S1 versus S2 or S3, radiologists had fair interreader agreement (0.30 [95% CI: 0.27, 0.33]), while AUCs were between 0.57 and 0.76 for radiologists and 0.73 (95% CI: 0.71, 0.75) for the deep learning model. For S2 or lower versus S3, radiologists had fair interreader agreement (0.37 [95% CI: 0.33, 0.40]), while AUCs were between 0.52 and 0.81 for radiologists and 0.67 (95% CI: 0.64, 0.69) for the deep learning model. Conclusion Deep learning approaches applied to B-mode US images provided comparable performance with human readers for detection and grading of hepatic steatosis. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Tuthill in this issue.

Purpose: A significant number of people will experience prolonged symptoms after COVID-19 infection that will greatly impact functional capacity and quality of life. The aim of this study was to identify trajectories of health-related quality of life (HRQOL) and their predictors among adults diagnosed with COVID-19., Methods: This is a retrospective analysis of an ongoing prospective cohort study (BQC-19) including adults (≥18y) recruited from April 2020 to March 2022. Our primary outcome is HRQOL using the EQ-5D-5L scale. Sociodemographic, acute disease severity, vaccination status, fatigue, and functional status at onset of the disease were considered as potential predictors. The latent class mixed model was used to identify the trajectories over an 18-month period in the cohort as a whole, as well as in the inpatient and outpatient subgroups. Multivariable and univariable regressions models were undertaken to detect predictors of decline., Results: 2163 participants were included. Thirteen percent of the outpatient subgroup (2 classes) and 28% in the inpatient subgroup (3 classes) experienced a more significant decline in HRQOL over time than the rest of the participants. Among all patients, age, sex, disease severity and fatigue, measured on the first assessment visit or on the first day after hospital admission (multivariable models), were identified as the most important predictors of HRQOL decline. Each unit increase in the SARC-F and CFS scores increase the likelihood of belonging to the declining trajectory (univariable models)., Conclusion: Although to different degrees, similar factors explain the decline in HRQOL over time among the overall population, people who have been hospitalized or not. Clinical functional capacity scales could help to determine the risk of HRQOL decline., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Positron emission tomography (PET) is a powerful imaging tool for drug discovery, clinical diagnosis, and monitoring of disease progression. Fluorine-18 is the most common radionuclide used for PET, but advances in radiotracer development have been limited by the historical lack of methodologies and precursors amenable to radiolabeling with fluorine-18. Radiolabeling of electron-rich (hetero)aromatic rings remains a long-standing challenge in the production of PET radiopharmaceuticals. In this personal account, we discuss the history of spirocyclic iodonium ylide precursors, from inception to applications in clinical research, for the incorporation of fluorine-18 into complex non-activated (hetero)aromatic rings., (© 2023 The Authors. The Chemical Record published by The Chemical Society of Japan and Wiley-VCH GmbH.)

Background: Preconditioning deceased organ donors with calcineurin inhibitors (CNIs) may reduce ischemia-reperfusion injury to improve transplant outcomes., Methods: We searched MEDLINE, EMBASE, Cochrane Library, and conference proceedings for animal models of organ donation and transplantation, comparing donor treatment with CNIs with either placebo or no intervention, and evaluating outcomes for organ transplantation. Reviewers independently screened and selected studies, abstracted data, and assessed the risk of bias and clinical relevance of included studies. Where possible, we pooled results using meta-analysis; otherwise, we summarized findings descriptively., Results: Eighteen studies used various animals and a range of CNI agents and doses and evaluated their effects on a variety of transplant outcomes. The risk of bias and clinical applicability were poorly reported. Pooled analyses suggested benefit of CNI treatment on early graft function in renal transplants (3 studies; serum creatinine: ratio of means [RoM] 0.54; 95% confidence interval [CI], 0.34-0.86) but not for liver transplants (2 studies; serum alanine transaminase: RoM 0.61; 95% CI, 0.30-1.26; and serum aspartate aminotransferase: RoM 0.58; 95% CI, 0.26-1.31). We found no reduction in graft loss at 7 d (2 studies; risk ratio 0.54; 95% CI, 0.08-3.42). CNI treatment was associated with reduced transplant recipient levels of interleukin-6 (4 studies; RoM 0.36; 95% CI, 0.19-0.70), tumor necrosis factor-alpha (5 studies; RoM 0.36; 95% CI, 0.12-1.03), and cellular apoptosis (4 studies; RoM 0.30; 95% CI, 0.19-0.47)., Conclusions: Although this compendium of animal experiments suggests that donor preconditioning with CNIs may improve early kidney graft function, the limited ability to reproduce a true clinical environment in animal experiments and to assess for risk of bias in these experiments is a serious weakness that precludes current clinical application., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

The integration of illness severity and organ dysfunction scores into clinical practice, including the APACHE II and SOFA scores, has been challenging due to constraints associated to manual score calculation. With electronic medical records (EMR), score calculation automation using data extraction scripts has emerged as a solution. We aimed to demonstrate that APACHE II and SOFA scores calculated with an automated EMR-based data extraction script predict important clinical endpoints. In this retrospective cohort study, every adult patient admitted to one of our three ICUs, between July 1, 2019, and December 31, 2020, were enrolled. For every patient, an automated ICU admission APACHE II score was calculated using EMR data and minimal clinician input. Fully automated daily SOFA scores were calculated for every patient. 4 794 ICU admissions met our selection criteria. Of these ICU admissions, 522 deaths were recorded (10.9% in-hospital mortality rate). The automated APACHE II was discriminant for in-hospital mortality (AU-ROC = 0.83 (95% CI 0.81-0.85)). We observed an association between the APACHE II score and ICU LOS, with a statistically significant mean increase of 1.1 days of ICU LOS (1.1 [1-1.2]; p =  < .0001) for each 10 units increase in APACHE score. SOFA score curves did not discrimate significantly between survivors and non-survivors. A partially automated APACHE II score, calculated with real-world EMR data using an extraction script, is associated with in-hospital mortality risk. The automated APACHE II score could potentially constitute an acceptable surrogate of ICU acuity to be used in resource allocation and triaging, especially in time of high demand for ICU beds., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Compared to younger age, older age (≥ 65 yr) is associated with worse outcomes after severe traumatic brain injury (TBI). We sought to describe the association of older age with in-hospital death and aggressiveness of intervention., Methods: We conducted a retrospective cohort study of adult (age ≥ 16 yr) patients with severe TBI admitted to a single academic tertiary care neurotrauma centre between January 2014 and December 2015. We collected data through chart review as well as from our institutional administrative database. We provided descriptive statistics and used multivariable logistic regression to evaluate the independent association of age with the primary outcome, in-hospital death. The secondary outcome was early withdrawal of life-sustaining therapy., Results: There were 126 adult patients (median age 67 yr [Q1-Q3, 33-80 yr]) with severe TBI during the study period who met our eligibility criteria. The most common mechanism was high-velocity blunt injury (55 patients [43.6%]). The median Marshall score was 4 (Q1-Q3, 2-6), and the median Injury Severity Score was 26 (Q1-Q3, 25-35). After controlling for confounders including clinical frailty, pre-existing comorbidity, injury severity, Marshall score and neurologic examination at admission, we observed that older patients were more likely than younger patients to die in hospital (odds ratio 5.10, 95% confidence interval 1.65-15.78). Older patients were also more likely to experience early withdrawal of life-sustaining therapy and less likely to receive invasive interventions., Conclusion: After controlling for confounding factors relevant to older patients, we observed that age was an important and independent predictor of in-hospital death and early withdrawal of life-sustaining therapy. The mechanism by which age influences clinical decision-making independent of global and neurologic injury severity, clinical frailty and comorbidities remains unclear., Competing Interests: Competing interests: At the time of acceptance, Victoria Saigle was affiliated with the CMAJ Group; however, she was not involved in any tasks related to the Canadian Journal of Surgery. Michael Chassé reports payment for expert testimony. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Purpose: The objective of this study was to describe some components of the perioperative practice in liver transplantation as reported by clinicians., Methods: We conducted a cross-sectional clinical practice survey using an online instrument containing questions on selected themes related to the perioperative care of liver transplant recipients. We sent email invitations to Canadian anesthesiologists, Canadian surgeons, and French anesthesiologists specialized in liver transplantation. We used five-point Likert-type scales (from "never" to "always") and numerical or categorical answers. Results are presented as medians or proportions., Results: We obtained answers from 130 participants (estimated response rate of 71% in Canada and 26% in France). Respondents reported rarely using transesophageal echocardiography routinely but often using it for hemodynamic instability, often using an intraoperative goal-directed hemodynamic management strategy, and never using a phlebotomy (medians from ordinal scales). Fifty-nine percent of respondents reported using a restrictive fluid management strategy to manage hemodynamic instability during the dissection phase. Forty-two percent and 15% of respondents reported using viscoelastic tests to guide intraoperative and postoperative transfusions, respectively. Fifty-four percent of respondents reported not pre-emptively treating preoperative coagulations disturbances, and 91% reported treating them intraoperatively only when bleeding was significant. Most respondents (48-64%) did not have an opinion on the maximal graft ischemic times. Forty-seven percent of respondents reported that a piggyback technique was the preferred vena cava anastomosis approach., Conclusion: Different interventions were reported to be used regarding most components of perioperative care in liver transplantation. Our results suggest that significant equipoise exists on the optimal perioperative management of this population., (© 2023. Canadian Anesthesiologists' Society.)

Positron emission tomography (PET) is a powerful tool for imaging biological processes in the central nervous system (CNS). Designing PET radiotracers capable of crossing the blood-brain barrier (BBB) remains a major challenge. In addition to being brain-penetrant, a quantifiable CNS PET radiotracer must have high target affinity and selectivity, appropriate pharmacokinetics, minimal non-specific binding, negligible radiometabolites in the brain, and generally must be amenable to labeling with carbon-11 ( 11 C) or fluorine-18 ( 18 F). This review aims to give an overview of some of the critical physicochemical and biochemical contributors specific for CNS PET radiotracer design and how they can differ from pharmaceutical drug development, including in vitro assays, in silico predictions, and in vivo studies, with examples for how such methods can be implemented to optimize brain uptake of radiotracers based on experiences from our neuroimaging program., (© 2023 John Wiley & Sons, Ltd.)

Stress-activated kinases are targets of interest in neurodegenerative disease due to their involvement in inflammatory signaling and synaptic dysfunction. The p38α kinase has shown clinical and preclinical promise as a druggable target in several neurodegenerative conditions. We report the radiosynthesis and evaluation of the first positron emission tomography (PET) radiotracer for imaging MAPK p38α/β through radiolabeling of the inhibitor talmapimod (SCIO-469) with carbon-11. [ 11 C]Talmapimod was reliably synthesized by carbon-11 methylation with non-decay corrected radiochemical yields of 3.1 ± 0.7%, molar activities of 38.9 ± 13 GBq/μmol, and >95% radiochemical purity ( n = 20). Preclinical PET imaging in rodents revealed a low baseline brain uptake and retention with standardized uptake values (SUV) of ∼0.2 over 90 min; however, pretreatment with the P-glycoprotein (P-gp) drug efflux transporter inhibitor elacridar enabled [ 11 C]talmapimod to pass the blood-brain barrier (>1.0 SUV) with distinct sex differences in washout kinetics. Blocking studies with a structurally dissimilar p38α/β inhibitor, neflamapimod (VX-745), and displacement imaging studies with talmapimod were attempted in elacridar-pretreated rodents, but neither compound displaced radiotracer uptake in the brain of either sex. Ex vivo radiometabolite analysis revealed substantial differences in the composition of radioactive species present in blood plasma but not in brain homogenates at 40 min post radiotracer injection. Digital autoradiography in fresh-frozen rodent brain tissue confirmed that the radiotracer signal was largely non-displaceable in vitro , where self-blocking and blocking with neflamapimod marginally decreased the total signal by 12.9 ± 8.8% and 2.66 ± 2.1% in C57bl/6 healthy controls and 29.3 ± 2.7% and 26.7 ± 12% in Tg2576 rodent brains, respectively. An MDCK-MDR1 assay suggests that talmapimod is likely to suffer from drug efflux in humans as well as rodents. Future efforts should focus on radiolabeling p38 inhibitors from other structural classes to avoid P-gp efflux and non-displaceable binding.