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Cerium and its derivatives have been used as remedies for wounds since the early 20th century. Cerium nitrate has attracted most attention in the treatment of deep burns, followed later by reports of its antimicrobial properties. Its ability to mimic and replace calcium is presumed to be a major mechanism of its beneficial action. However, despite some encouraging results, the overall data are somewhat confusing with seemingly the same compounds yielding opposing results. Despite this, cerium nitrate is currently used in wound treatment in combination with silver sulfadiazine as Flammacérium. Cerium oxide, especially in nanoparticle form (Nanoceria), has lately captured much interest due to its antibacterial properties mediated via oxidative stress, leading to an increase of published reports. The properties of Nanoceria depend on the synthesis method, their shape and size. Recently, the green synthesis route has gained a lot of interest as an alternative environmentally friendly method, resulting in production of effective antimicrobial and antifungal nanoparticles. Unfortunately, as is the case with antibiotics, emerging bacterial resistance against cerium-derived nanoparticles is a growing concern, especially in the case of bacterial biofilm. However, diverse strategies resulting from better understanding of the biology of cerium are promising. The aim of this paper is to present the progress to date in the use of cerium compounds as antimicrobials in clinical applications (in particular wound healing) and to provide an overview of the mechanisms of action of cerium at both the cellular and molecular level.

Severe trauma induces a widespread response of the immune system. This \"genomic storm\" can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS. We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] ≥ 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS ≤ 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts. In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response.

The UK stillbirth rate remains higher than in many high-income countries, with placental disorders -particularly maternal vascular malperfusion (MVM) lesions -linked to adverse maternal and fetal outcomes. This study examines placental lesions in stillbirth at one of the largest maternity units in the UK using the Amsterdam criteria for histological classification. It also retrospectively examines whether women with global/partial MVM - where most maternal decidual vessels show pathological changes but are only partially occluded- would have received aspirin and further surveillance if their placental dysfunction risk had been assessed using the Fetal Medicine Foundation (FMF) algorithm from the Tommy's app in their first trimester. We conducted a case-control study of spontaneous non-anomalous stillbirths (≥24 weeks) at Sheffield maternity unit from 2018 to 2021 (n = 83). We then compared singleton stillbirths at term with matched livebirths. Placental lesions were categorised with the Amsterdam criteria. Using the FMF's algorithm which has only been recently introduced in our unit, we then retrospectively calculated the risk for placental dysfunction in women who experienced preterm PET stillbirth and also in those whose placentas showed global/partial MVM. MVM was the most common placental lesion in stillbirths, significantly more frequent than in livebirths (p < 0.001). The FMF algorithm had higher predictive accuracy for PET than the traditional NICE model in stillbirths [AUC: 0.76 (95% CI 0.65-0.86) vs 0.51 (95% CI 0.39-0.63), p = 0.03], but only when at least one continuous variable such as PAPP-A was included. In women with stillbirth and whose placentas showed global/partial MVM, first-trimester placental risk assessment using the FMF algorithm during the first trimester would have identified most of them as high risk [FMF AUC: 0.7 (0.58-0.80), p = 0.02]. MVM is frequently found in stillbirths. Our retrospective placental dysfunction risk assessment suggests that Tommy's algorithm would have more accurately identified women who went onto experience stillbirth with significant MVM lesions as high risk, leading to aspirin treatment and closer monitoring. Further research is needed to confirm these findings and potentially enhance placental dysfunction screening to reduce stillbirth rates.

This study shows that the political preferences of those responsible for retaining judges are strongly associated with judicial voting. The evidence supports the widespread belief that judges respond to political pressure in an effort to be reelected or reappointed. Using a data set of decisions in state supreme courts from 1995–98, I find that state supreme court judges who face retention decisions by Republicans tend to decide cases in accord with standard Republican policy. Judicial behavior is correspondingly liberal for judges facing retention decisions by Democrats. The results are strongest for judges facing partisan reelections. Among judges with conservative fundamental ideologies, those facing Democratic retention agents vote more liberally than those facing Republican retention agents. Similarly, judges’ voting changes when the political preferences of the retention agents change. Judges with permanent tenure and judges in their last term do not respond to the same forms of political pressure.

The idea that wealthy people use their money to influence things, including politics, law, and media will surprise very few people. However, as Michael S. Kang and Joanna Shepherd argue in this readable and rich study of the state judiciary, the effect of money on judicial outcomes should disturb and anger everyone. In the current system that elects state judges, the rich and powerful can spend money to elect and re-elect judges who decide cases the way they want. Free to Judge is about how and why money increasingly affects the dispensation of justice in our legal system, and what can be done to stop it. One of the barriers to action in the past has been an inability to prove that campaign donations influence state judicial decision-making. In this book, Kang and Shepherd answer that challenge for the first time, with a rigorous empirical study of campaign finance and judicial decision-making data. Pairing this with interviews of past and present judges, they create a compelling and persuasive account of people like Marsha Ternus, the first Iowa state supreme court justice to be voted out of office after her decision in a same-sex marriage case. The threat of such an outcome, and the desire to win reelection, results in judges demonstrably leaning towards the interests and preferences of their campaign donors across all cases. Free to Judge is thus able to identify the pieces of our current system that invite bias, such as judicial reelection, and what reforms should focus on. This thoughtful and compellingly written book will be required reading for anybody who cares about creating a more just legal system.

PurposeThis study aimed at determining whether intravenous artesunate is safe and effective in reducing multiple organ dysfunction syndrome in trauma patients with major hemorrhage.MethodsTOP-ART, a randomized, blinded, placebo-controlled, phase IIa trial, was conducted at a London major trauma center in adult trauma patients who activated the major hemorrhage protocol. Participants received artesunate or placebo (2:1 randomization ratio) as an intravenous bolus dose (2.4 mg/kg or 4.8 mg/kg) within 4 h of injury. The safety outcome was the 28-day serious adverse event (SAE) rate. The primary efficacy outcome was the 48 h sequential organ failure assessment (SOFA) score. The per-protocol recruitment target was 105 patients.ResultsThe trial was terminated after enrolment of 90 patients because of safety concerns. Eighty-three participants received artesunate (n = 54) or placebo (n = 29) and formed the safety population and 75 met per-protocol criteria (48 artesunate, 27 placebo). Admission characteristics were similar between groups (overall 88% male, median age 29 years, median injury severity score 22), except participants who received artesunate were more shocked (median base deficit 9 vs. 4.7, p = 0.042). SAEs occurred in 17 artesunate participants (31%) vs. 5 who received placebo (17%). Venous thromboembolic events (VTE) occurred in 9 artesunate participants (17%) vs. 1 who received placebo (3%). Superiority of artesunate was not supported by the 48 h SOFA score (median 5.5 artesunate vs. 4 placebo, p = 0.303) or any of the trial’s secondary endpoints.ConclusionAmong critically ill trauma patients, artesunate is unlikely to improve organ dysfunction and might be associated with a higher VTE rate.

Bush v. Gore decided a presidential election and is the most dramatic election case in our lifetime, but cases like it are decided every year at the state level. Ordinary state courts regularly decide questions of election rules and administration that effectively determine electoral outcomes hanging immediately in the balance. Election cases like Bush v. Gore embody a fundamental worry with judicial intervention into the political process: outcome-driven, partisan judicial decisionmaking. The Article investigates whether judges decide cases, particularly politically sensitive ones, based on their partisan loyalties more than the legal merits of the cases. It presents a novel method to isolate the raw partisan motivations of judges and identifies their partisan loyalty, as opposed to their ideology, by studying a special category of cases: candidate-litigated election disputes. The Article finds that Republican judges display greater partisan loyalty than Democratic judges in election cases where ideology is not a significant consideration. This result is not a function of selection methods, with both elected and appointed judges behaving similarly, but is partially a function of party campaign finance for Republican elected judges, with party loyalty increasing with party money received. However, the effect of party money disappears for more visible election cases and for retiring judges in their final term. What is more, partisan loyalty diminishes when state supreme court elections feature more campaign attack advertising. These findings give reason to rethink judicial resolution of election disputes that require impartial, nonpartisan settlement and offer new insight into judicial partisanship as a more general matter.

Background Current predictive machine learning techniques for spontaneous preterm birth heavily rely on a history of previous preterm birth and/or costly techniques such as fetal fibronectin and ultrasound measurement of cervical length to the disadvantage of those considered at low risk and/or those who have no access to more expensive screening tools. Aims and objectives We aimed to develop a predictive model for spontaneous preterm delivery < 37 weeks using socio-demographic and clinical data readily available at booking -an approach which could be suitable for all women regardless of their previous obstetric history. Methods We developed a logistic regression model using seven feature variables derived from maternal socio-demographic and obstetric history from a preterm birth ( n  = 917) and a matched full-term ( n  = 100) cohort in 2018 and 2020 at a tertiary obstetric unit in the UK. A three-fold cross-validation technique was applied with subsets for data training and testing in Python® (version 3.8) using the most predictive factors. The model performance was then compared to the previously published predictive algorithms. Results The retrospective model showed good predictive accuracy with an AUC of 0.76 (95% CI: 0.71–0.83) for spontaneous preterm birth, with a sensitivity and specificity of 0.71 (95% CI: 0.66–0.76) and 0.78 (95% CI: 0.63–0.88) respectively based on seven variables: maternal age, BMI, ethnicity, smoking, gestational type, substance misuse and parity/obstetric history. Conclusion Pending further validation, our observations suggest that key maternal demographic features, incorporated into a traditional mathematical model, have promising predictive utility for spontaneous preterm birth in pregnant women in our region without the need for cervical length and/or fetal fibronectin.

[This corrects the article DOI: 10.1371/journal.pmed.1002352.].

The physiological wound healing process involves a cascade of events which could be affected by several factors resulting in chronic, non-healing wounds. The latter represent a great burden especially when bacterial biofilms are formed. The rise in antibiotic resistance amongst infectious microorganisms leads to the need of novel approaches to treat this clinical issue. In this context, the use of advanced biomaterials, which can enhance the physiological expression and secretion of the growth factors involved in the wound healing process, is gaining increasing attention as a robust and appealing alternative approach. Among them, mesoporous glasses are of particular interest due to their excellent textural properties and to the possibility of incorporating and releasing specific therapeutic species, such as metallic ions. One of the most attractive therapeutic ions is copper thanks to its proangiogenic and antibacterial effects. In this contribution, copper containing mesoporous glass nanoparticles were proposed as a multifunctional device to treat chronic wounds. The developed nanoparticles evidenced a very high specific surface area (740 m /g), uniform pores of 4 nm and an almost total release of the therapeutic ion within 72 h of soaking. The produced nanoparticles were biocompatible and, when tested against Gram positive and Gram negative bacterial species, demonstrated antibacterial activity against both planktonic and biofilm bacteria in 2D cell monolayers, and in a 3D human model of infected skin. Their proangiogenic effect was tested with both the aortic ring and the chick chorioallantoic membrane assays and an increase in endothelial cell outgrowth at a concentration range between 30 and 300 ng/mL was shown. Overall, in this study biocompatible, multifunctional Cu-containing mesoporous glass nanoparticles were successfully produced and demonstrated to exert both antibacterial and proangiogenic effects.