Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs.

The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite's food vacuoles, our approach is summarized as "to dig its grave with its fork". However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.

Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader-Willi Syndrome.

The eutherian-specific SNORD116 family of repeated box C/D snoRNA genes is suspected to play a major role in the Prader-Willi syndrome (PWS), yet its molecular function remains poorly understood. Here, we combined phylogenetic and molecular analyses to identify candidate RNA targets. Based on the analysis of several eutherian orthologs, we found evidence of extensive birth-and-death and conversion events during SNORD116 gene history. However, the consequences for phylogenetic conservation were heterogeneous along the gene sequence. The standard snoRNA elements necessary for RNA stability and association with dedicated core proteins were the most conserved, in agreement with the hypothesis that SNORD116 generate genuine snoRNAs. In addition, one of the two antisense elements typically involved in RNA target recognition was largely dominated by a unique sequence present in at least one subset of gene paralogs in most species, likely the result of a selective effect. In agreement with a functional role, this ASE exhibited a hybridization capacity with putative mRNA targets that was strongly conserved in eutherians. Moreover, transient downregulation experiments in human cells showed that Snord116 controls the expression and splicing levels of these mRNAs. The functions of two of them, diacylglycerol kinase kappa and Neuroligin 3, extend the description of the molecular bases of PWS and reveal unexpected molecular links with the Fragile X syndrome and autism spectrum disorders.

Hybrid molecules based on an emodin scaffold. Synthesis and activity against SARS-CoV-2 and Plasmodium.

Since the Covid-19 epidemic, it has been clear that the availability of small and affordable drugs that are able to efficiently control viral infections in humans is still a challenge in medicinal chemistry. The synthesis and biological activities of a series of hybrid molecules that combine an emodin moiety and other structural moieties expected to act as possible synergistic pharmacophores in a single molecule were studied. Emodin has been reported to block the entry of the SARS-CoV-2 virus into human cells and might also inhibit cytokine production, resulting in the reduction of pulmonary injury induced by SARS-CoV-2. The pharmacophore associated with emodin was either a polyamine residue (emodin-PA series), a choice driven by the fact that a natural alkyl PA like spermine and spermidine play regulatory roles in immune cell functions, or a diphenylmethylpiperazine derivative of the norchlorcyclizine series (emoxyzine series). In fact, diphenylmethylpiperazine antagonists of the H1 histamine receptor display activity against several viruses by multiple interrelated mechanisms. In the emoxyzine series, the most potent drug against SARS-CoV-2 was (R)-emoxyzine-2, with an EC50 value = 1.9 µM, which is in the same range as that of the reference drug remdesivir. However, the selectivity index was rather low, indicating that the dissociation of antiviral potency and cytotoxicity remains a challenge. In addition, since emodin was also reported to be a relatively high-affinity inhibitor of the virulence regulator FIKK kinase from the malaria parasite Plasmodium vivax, the antimalarial activity of the synthesized hybrid compounds has been evaluated. However, these molecules cannot efficiently compete with the currently used antimalarial drugs.

Removing the language barrier in the medical care of allophone patients / Lever de la barrière linguistique dans la prise en charge médicale de patients allophones

INTRODUCTION: Non-French speaking patients have difficulty communicating with professionals when they come to a health care service. The role of the nursing staff is thus to find solutions to communicate effectively with them and facilitate patient care. PURPOSE OF RESEARCH: A systematic search of medical and allied health databases was conducted (EM Premium, BDSP, PubMed, Cairn.info). Articles identified during the search process that met the inclusion criteria were then critically appraised. RESULTS: During the search and inclusion process, 13 articles, 3 systematic review and 2 randomized control trials were found that were deemed of suitable quality to be included in the review. These were analyzed in more detail to observe common themes and then grouped into three categories. CONCLUSIONS: The results of the review demonstrate the different techniques used in care to overcome the language barrier and their effectiveness. All health care professionals involved in care must be familiar with the different techniques used and their usefulness.

Introduction: Lorsque les patients allophones se présentent dans un service de soins, le rôle du personnel soignant est de trouver des solutions pour communiquer efficacement avec eux. But de l'étude: Cette scoping review a pour but de retranscrire les différentes techniques utilisées dans les soins pour pallier la barrière linguistique, de les comparer et d'évaluer leur efficacité. Une recherche systématique de la littérature a été effectuée à l'aide de bases de données (EM Premium, BDSP, PubMed, Cairn.info) pour des publications comprises entre 2005 à 2021 en utilisant des termes de recherche pertinents. Résultats: Au total, 13 articles ont pu être étudiés et confrontés entre eux. Ils ont été regroupés en trois catégories différentes : 1) interprètes professionnels, 2) interprètes non professionnels, 3) autres méthodes. La plupart des articles ont relevé certains avantages au fait que les professionnels médicaux utilisent une technique pour pallier la barrière de la langue. Conclusions: Malgré la faible quantité de publications sur le sujet et le manque de mesures standardisées dans les articles inclus, cette revue établit suffisamment de données pour conclure que les stratégies mises en place pour pallier la barrière linguistique dans les soins sont efficaces.

Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria.

Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties on DNA methyltransferases and HDAC's for epigenetics, and on cytochrome bc1 and dihydroorotate dehydrogenase for mitochondrion.

Metal Ions in Alzheimer's Disease: A Key Role or Not?

Despite tremendous research efforts in universities and pharmaceutical companies, effective drugs are still lacking for the treatment of Alzheimer's disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease have not yet been clearly understood. Besides a small percentage of cases with early onset disease having a genetic origin (<5%, familial AD), most cases develop in the elderly as a sporadic form due to multiple and complex parameters of aging. Consequently, AD is spreading in all countries with a long life expectancy. AD is characterized by deposition of senile plaques made of ß-amyloid proteins (Aß) and by hyperphosphorylation of tau proteins, which have been considered as the main drug targets up to now. However, antibodies targeting amyloid aggregates, as well as enzyme inhibitors aiming to modify the amyloid precursor protein processing, have failed to improve cognition in clinical trials. Thus, to set up effective drugs, it is urgent to enlarge the panel of drug targets. Evidence of the link between AD and redox metal dysregulation has also been supported by post-mortem analyses of amyloid plaques, which revealed accumulation of copper, iron, and zinc by 5.7, 2.8, and 3.1 times, respectively, the levels observed in normal brains. Copper-amyloid complexes, in the presence of endogenous reductants, are able to catalyze the reduction of dioxygen and to produce reduced, reactive oxygen species (ROS), leading to neuron death. The possibility of using metal chelators to regenerate normal trafficking of metal ions has been considered as a promising strategy in order to reduce the redox stress lethal for neurons. However, most attempts to use metal chelators as therapeutic agents have been limited to existing molecules available from the shelves. Very few chelators have resulted from a rational design aiming to create drugs with a safety profile and able to cross the blood-brain barrier after an oral administration. In the human body, metals are handled by a sophisticated protein network to strictly control their transport and reactivity. Abnormal concentrations of certain metals may lead to pathological events due to misaccumulation and irregular reactivity. Consequently, therapeutic attempts to restore metal homeostasis should carefully take into account the coordination chemistry specificities of the concerned redox-active metal ions. This Account is focused on the role of the main biologically redox-active transition metals, iron and copper. For iron, the recent debate on the possible role of magnetite in AD pathogenesis is presented. The section devoted to copper is focused on the design of specific copper chelators as drug candidates able to regulate copper homeostasis and to reduce the oxidative damage responsible for the neuron death observed in AD brains. A short survey on non-redox-active metal ions is also included at the beginning, such as aluminum and its controversial role in AD and zinc which is a key metal ion in the brain.

Involvement of Pazopanib and Sunitinib Aldehyde Reactive Metabolites in Toxicity and Drug-Drug Interactions in Vitro and in Patient Samples.

Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug-drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug-drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.

Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites.

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.

Endoperoxide-based compounds: cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism.

Background: Owing to the emergence of multiresistant Plasmodium falciparum parasites in Southeast Asia, along with the impressive decrease in the efficacy of the endoperoxide compound artemisinin and of artemisinin-based combination therapies, the development of novel antimalarial drugs or combinations is required. Although several antiplasmodial molecules, such as endoperoxide-based compounds, are in advanced research or development, we do not know whether resistance to artemisinin derivatives might impact the efficacy of these new compounds. Objectives: To address this issue, the antiplasmodial efficacy of trioxaquines, hybrid endoperoxide-based molecules, was explored, along with their ability to select in vitro resistant parasites under discontinuous and dose-escalating drug pressure. Methods: The in vitro susceptibilities of artemisinin- and trioxaquine-resistant laboratory strains and recent Cambodian field isolates were evaluated by different phenotypic and genotypic assays. Results: Trioxaquines tested presented strong cross-resistance with artemisinin both in the artemisinin-resistant laboratory F32-ART5 line and in Cambodian field isolates. Trioxaquine drug pressure over 4 years led to the in vitro selection of the F32-DU line, which is resistant to trioxaquine and artemisinin, similar to the F32-ART lineage. F32-DU whole genome sequencing (WGS) revealed that resistance to trioxaquine was associated with the same non-synonymous mutation in the propeller domain of the K13 protein (M476I) that was found in the F32-ART lineage. Conclusions: These worrisome results indicate the risk of cross-resistance between artemisinins and endoperoxide-based antiplasmodial drugs in the development of the K13 mutant parasites and question the usefulness of these molecules in the future therapeutic arsenal.

N4 -Tetradentate Chelators Efficiently Regulate Copper Homeostasis and Prevent ROS Production Induced by Copper-Amyloid-ß1-16.

The disruption of copper homeostasis and the oxidative stress induced by Cu-amyloids are crucial features of Alzheimer's disease pathology. The copper specific N4 -tetradendate ligands TDMQ20 and 1 are able to fully inhibit in vitro the aerobic oxidation of ascorbate induced by Cu-Aß1-16 , even in the presence of 100 molar equivalents of ZnII with respect to CuII , whereas other ligands with N2 O2 or N3 O2 coordination spheres failed to do so. This essential result indicates that, in addition to metal selectivity, the coordination sphere of copper chelators should exhibit a N4 -tetradendate motif to be able to reduce an oxidative stress in the zinc-rich physiological environment of brain. The N4 -scaffolds of these two aminoquinoline-based ligands, TDMQ20 or 1, suitable for a square-planar coordination of copper(II), allowed them to enhance both the selectivity for copper and the ability to reduce the oxidative stress induced by copper-amyloid in a zinc-rich environment.

Magnetite Fe3 O4 Has no Intrinsic Peroxidase Activity, and Is Probably not Involved in Alzheimer's Oxidative Stress.

Despite stated in some highly cited articles, magnetite is devoided of peroxidase activity. In fact, this very stable mixed valence FeII O⋅FeIII2 O3 complex is not catalytically competent to oxidize standard peroxidase substrates, especially at the biologically relevant pH value of 7.4. In addition, magnetite whose deleterious redox activity has been suspected in Alzheimer's disease brain damages, does not significantly interact with amyloid peptide Aß in vitro, and is not able to induce, either in the presence or absence of Aß, the reductive activation of dioxygen, the first step of an oxidative stress. In fact, this highly insoluble mineral iron derivative is probably not involved in the oxidative damage of brain neurons of patients with AD.

Synthesis of a library of variously modified 4-methylumbelliferyl xylosides and a structure-activity study of human ß4GalT7.

Proteoglycans (PGs) are complex macromolecules that are composed of glycosaminoglycan (GAG) chains covalently attached to a core protein through a tetrasaccharide linker. The biosynthesis of PGs is complex and involves a large number of glycosyltranferases. Here we present a structure-activity study of human ß4GalT7, which transfers the first Gal residue onto a xyloside moiety of the linkage region. An efficient and regiocontrolled synthesis of a library of modified analogs of 4-methylumbelliferyl xyloside (XylMU) is reported herein. Hydroxyl groups at the position C-2, C-3 or C-4 have been epimerized and/or replaced by a hydrogen or a fluorine, while the anomeric oxygen was replaced by either a sulfur or a sulfone. The effect of these compounds on human ß4GalT7 activity in vitro and on GAG biosynthesis in cellulo was then evaluated.

[« Doctor, I would like to stay at home ¼ About the partnership between a specialized palliative home care team and general practitioners]. / « J'aimerais rester chez moi, Docteur ¼. A propos du partenariat entre l'équipe mobile de soinspalliatifs et les médecins de premier recours.

During home care, general practitioners are faced with complex end-of-life situations. This leads to difficulties in taking care of the patient alone, and may require support from a multi-professional specialized palliative home care team. The palliative care teams follow these situations upon request from the GPs or home nurses, in order to provide help in encountered difficulties. The palliative care teams' activity is based on mentoring, anticipating possible future difficulties and managing crises. In order to have a real working partnership between the home palliative care teams and the GPs it is essential to have a mutual understanding of how each entity works and what kind of help they can provide.

Les médecins de premier recours peuvent être confrontés au domicile à des situations de fin de vie lourdes et complexes, difficiles à prendre en charge seuls, dans lesquelles le soutien d'une équipe multi-professionnelle spécialisée en soins palliatifs est nécessaire. L'équipe mobile de soins palliatifs intervient sur demande des médecins et des équipes soignantes pour les aider à faire face à ces difficultés. Son activité est centrée sur le compagnonnage de ces équipes par une aide à l'anticipation et à la gestion de la crise. Un partenariat efficace entre l'équipe mobile de soins palliatifs et les médecins de premier recours implique une connaissance réciproque, à la fois du fonctionnement et des prestations offertes par chacun des partenaires.

Regulation of copper and iron homeostasis by metal chelators: a possible chemotherapy for Alzheimer's disease.

With the increase of life expectancy of humans in more than two-thirds of the countries in the World, aging diseases are becoming the frontline health problems. Alzheimer's disease (AD) is now one of the major challenges in drug discovery, since, with the exception of memantine in 2003, all clinical trials with drug candidates failed over the past decade. If we consider that the loss of neurons is due to a high level of oxidative stress produced by nonregulated redox active metal ions like copper linked to amyloids of different sizes, regulation of metal homeostasis is a key target. The difficulty for large copper-carrier proteins to directly extract copper ions from metalated amyloids might be considered as being at the origin of the rupture of the copper homeostasis regulation in AD brains. So, there is an urgent need for new specific metal chelators that should be able to regulate the homeostasis of metal ions, specially copper and iron, in AD brains. As a consequence of that concept, chelators promoting metal excretion from brain are not desired. One should favor ligands able to extract copper ions from sinks (amyloids being the major one) and to transfer these redox-active metal ions to copper-carrier proteins or copper-containing enzymes. Obviously, the affinity of these chelators for the metal ion should not be a sufficient criterion, but the metal specificity and the ability of the chelators to release the metal under specific biological conditions should be considered. Such an approach is still largely unexplored. The requirements for the chelators are very high (ability to cross the brain-blood barrier, lack of toxicity, etc.), few chemical series were proposed, and, among them, biochemical or biological data are scarce. As a matter of fact, the bioinorganic pharmacology of AD represents less than 1% of all articles dedicated to AD drug research. The major part of these articles deals with an old and rather toxic drug, clioquinol and related analogs, that do not efficiently extract copper from soluble amyloids. We have designed and developed new tetradendate ligands such as 21 and PA1637 based on bis(8-aminoquinolines) that are specific for copper chelation and are able to extract copper(II) from amyloids and then can release copper ion upon reduction with a biological reducing agent. These studies contribute to the understanding of the physicochemical properties of the tetradentate copper ligands compared with bidentate ligands like clioquinol. One of these copper ligands, PA1637, after selection with a nontransgenic mouse model that is able to efficiently monitor the loss of episodic memory, is currently under preclinical development.

Transfer of Copper from an Amyloid to a Natural Copper-Carrier Peptide with a Specific Mediating Ligand.

The oxidative stress that arises from the catalytic reduction of dioxygen by Cu(II/I)-loaded amyloids is the major pathway for neuron death that occurs in Alzheimer's disease. In this work, we show that bis-8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu(II) from Cu-Aß1-16 and then completely release Cu(I) in the presence of glutathione to provide a Cu(I)-glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper-protein complexes. These data demonstrate that bis-8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu-amyloid complexes to regular copper-protein complexes. These copper-specific ligands assist GSH to recycle Cu(I) in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer's disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8-hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu-ß-amyloid complexes.

Extracorporeal Membrane Oxygenation in Pregnancy.

AIM: Adult respiratory distress syndrome (ARDS) may pose specific challenges in pregnant women, including the need for prone decubitus ventilation and extracorporeal membrane oxygenation (ECMO). We present our experience with ECMO during pregnancy and review the literature on this topic. METHODS: We performed a systematic literature review using the MEDLINE-NIH database. Papers describing single cases or clinical series of pregnant women treated with veno-venous ECMO for ARDS were retrieved; the clinical features and maternal and infant outcomes were presented in aggregate form. RESULTS: We describe the case of a 32-year-old primigravida who received ECMO starting at the 28th gestation week due to A/H1N1 influenza-related ARDS. This strategy allowed saving both mother and child; normal recovery without sequelae was evident at one year. The systematic review included 29 reported cases of ECMO employment during pregnancy; A/H1N1 influenza was the etiology of ARDS in 79% of cases. Maternal and infant mortality may reach 28%, while the rate of complications during ECMO support reaches 57%. CONCLUSIONS: ECMO is a viable treatment for severe ARDS during pregnancy, after failure of other therapeutic strategies; the risk of spontaneous gynecological bleeding is limited. Issues remain about the timing of ECMO implantation and the management of gestation. Close fetal assessment and multidisciplinary discussion are pivotal for decision-making.

Characterization of new specific copper chelators as potential drugs for the treatment of Alzheimer's disease.

The non-controlled redox-active metal ions, especially copper, in the brain of patients with Alzheimer disease (AD) should be considered at the origin of the intense oxidative damage in the AD brain. Several bis(8-aminoquinoline) ligands, such as 1 and PA1637, are able to chelate Cu(2+) with high affinity, and are specific chelators of copper with respect to iron and zinc. They are able to efficiently extract Cu(2+) from a metal-loaded amyloid. In addition, these tetradentate ligands are specific for the chelation of Cu(2+) compared with Cu(+). Consequently, the copper ion is easily released from the bis(8-aminoquinoline) ligand under reductive conditions, and can be trapped again by a protein having some affinity for copper such as human serum albumin (HSA) proteins. In addition, the copper is not efficiently released from [Cu(CQ)2] in reductive conditions. The catalytic production of H2O2 by [Cu(2+)-Aß(1-28)]/ascorbate is inhibited in vitro by the bis(8-aminoquinoline) 1, suggesting that 1 should be able to play a protective role against oxidative damages induced by copper-loaded amyloids.

Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: "Digging Their Graves with Their Forks".

The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm's digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals-which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.

Value of 18 F-FDG PET/CT to Identify Occult Infection in Presumed Aseptic Pseudarthrosis after Spinal Fusion: Correlation with Intraoperative Cultures.

Objective Fluorine-18 fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) has gained attention as an emerging tool in case of suspicion of infection on spine, whether native or instrumented. However, the diagnostic performance of 18 F-FDG PET/CT in clinically occult low-grade surgical site infection (SSI) after spinal fusion, an important risk factor for pseudarthrosis, remains unknown. Methods We retrospectively identified all the presumed aseptic patients with pseudarthrosis confirmed by revision surgery who underwent preoperative 18 F-FDG PET/CT scans performed between April 2019 and November 2022. These patients were presumed aseptic because they did not have clinical signs or laboratory tests suggestive of SSI, preoperatively. The PET/CT images were analyzed in consensus by two nuclear medicine physicians blinded to the clinical, biological, and imaging information. Visual assessment of increased uptake around cage/intervertebral disk space (and/or hardware) higher than background recorded from the first normal adjacent vertebra was interpreted as positive. Image data were also quantitatively analyzed by the maximum standardized uptake value as an index of 18 F-FDG uptake, and the ratio between the uptake around cage/intervertebral disk space (and/or hardware) and background recorded from the first normal adjacent vertebra was calculated. The final diagnosis of infection was based on intraoperative cultures obtained during pseudarthrosis revision surgery. Results Thirty-six presumed aseptic patients with surgically confirmed pseudarthrosis after spinal fusion underwent preoperative 18 F-FDG PET/CT scans. Cultures of samples from revisions found that 20 patients (56%) were infected. The most frequent isolated bacterium was Cutibacterium acnes ( C. acnes ) in 15 patients (75%), followed by coagulase-negative staphylococci (CNS) in 7 patients (33%). Two patients had co-infections involving both C. acnes and CNS. Of the 36 PET/CT studied in this study, 12 scans were true-negative, 10 true-positive, 10 false-negative, and 4 false-positive. This resulted in sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 50%, 75%, 71%, 55%, and 61%, respectively. Conclusion In presumed aseptic pseudarthrosis after spinal fusion, 18 F-FDG PET/CT offers good specificity (75%) but low sensitivity (50%) to identify occult SSI. The high prevalence (56%) of SSI, mostly caused by C. acnes (75%), found in our presumed aseptic cohort of patients supports the utility of systematic intraoperative cultures in revision cases for pseudarthrosis.

Correlation between Plasmodium yoelii nigeriensis susceptibility to artemisinin and alkylation of heme by the drug.

Evidence of artemisinin (ART) resistance in all of the Greater Mekong Region is currently of major concern. Understanding of the mechanisms of resistance developed by Plasmodium against artemisinin and its derivatives is urgently needed. We here demonstrated that ART was able to alkylate heme in mice infected by the ART-susceptible strain of Plasmodium yoelii nigeriensis, Y-control. After long-term drug pressure, the parasite strain (Y-ART3) was 5-fold less susceptible to ART than Y-control. In the blood of mice infected by Y-ART3, no heme-artemisinin adducts could be detected. After release of ART drug pressure, the parasite strain obtained (Y-REL) regained both drug susceptibility to ART and increased ability to produce covalent heme-artemisinin adducts. The correlation between parasite ART susceptibility and alkylation of heme by the drug confirms that heme or hemozoin metabolism is a key target for efficacy of ART as an antimalarial.