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.

High Tyrosol and Hydroxytyrosol Intake Reduces Arterial Inflammation and Atherosclerotic Lesion Microcalcification in Healthy Older Populations.

Aging is an important risk factor for cardiovascular diseases and convincing data have shown that chronic low-grade inflammation, which develops with advanced age, contributes significantly to cardiovascular risk. The present study aimed to use 18F-FDG/18F-NaF-PET/CT imaging to, respectively, gauge arterial inflammation and microcalcification in a healthy elderly population and to assess the potential benefits of a tyrosol- and hydroxytyrosol-rich diet on these two markers of atherosclerotic plaque fragility. Eleven healthy participants (mean age 75 ± 5.67 years) were supplemented for 6 months with high polyphenol-rich extra virgin olive oil (HP-EVOO), extra virgin olive oil (EVOO), or refined olive oil (ROO). The participants underwent PET/CT imaging with 18F-FDG and 18F-NaF radiotracers at baseline and after 6 months. 18F-FDG and 18F-NaF uptakes were quantified using standardized uptake values (SUV) and were categorized based on artery calcification and olive oil type. A total of 324 slices of the aortas of the imaged participants were analyzed for arterial inflammation and 327 slices were analyzed for microcalcification. 18F-FDG uptake was significantly higher in the non-calcified segments than in the calcified segments (SUVmax = 2.70 ± 0.62 and SUVmax = 2.54 ± 0.44, respectively, p < 0.042). Conversely, the non-calcified segments displayed significantly lower 18F-NaF uptake than the calcified segments (SUVmax = 1.90 ± 0.37 and 2.09 ± 0.24, respectively, p < 0.0001). The 6-month supplementation with HP-EVOO induced a significant reduction in 18F-FDG uptake in both the non-calcified (2.93 ± 0.23 to 2.75 ± 0.38, p < 0.004) and calcified segments of the aortas (2.25 ± 0.29 to 2.15 ± 0.19, p < 0.02). 18F-NaF uptake was also significantly lower in patients supplemented with HP-EVOO (SUVmax = 1.98 ± 0.33 at baseline compared to 1.85 ± 0.28, after the 6-month supplementation, p < 0.004), whereas no significant effect was observed with EVOO. Conversely, participants supplemented with ROO displayed a significant increase in 18F-NaF uptake (SUVmax = 1.78 ± 0.34 to 1.95 ± 0.34, p < 0.0001). The present study confirmed that a phenolic-compound-rich diet reduces both arterial inflammation and atherosclerotic lesion microcalcification and demonstrated that 18F-FDG/18F-NaF-PET/CT imaging is a valuable approach for assessing age-related arterial damage.

The Specific Copper(II) Chelator TDMQ20 Is Efficient for the Treatment of Wilson's Disease in Mice.

(1) Background: In patients with Wilson's disease, the deficiency of the copper carrier ATP7B causes the accumulation of copper in the liver, brain and various other organs. Lifelong treatment is therefore mandatory, using copper chelators to increase the excretion of copper and to avoid life-threatening damage. The clinically used reference drug, D-penicillamine, exhibit numerous adverse effects, especially a frequent severe and irreversible neurological worsening, mainly due to its lack of metal selectivity; (2) Methods: A new tetradentate ligand based on an 8-aminoquinoline entity, named TDMQ20, which is highly selective for copper compared with other metal ions, is evaluated in "toxic milk" TX mice as an oral treatment of this Wilson's disease murine model; (3) Results: The concentration of copper in the liver of "toxic milk" TX mice decreased and the fecal excretion of copper increased upon oral treatment with TDMQ20. Both effects are dose-dependent, and more pronounced than those of D-penicillamine; (4) Conclusions: The TDMQ20 copper chelator is more efficient than the reference drug D-penicillamine for the treatment of a Wilson's disease murine model. Pharmacological data obtained with TDMQ20 on the TX mouse model strongly support the selection of this ligand as a drug candidate for this genetic disease.

Insulin Growth Factor-1 Status in Hidradenitis Suppurativa: A French Institutional Pilot Study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease of the follicles in the apocrine glands and is associated with a deficiency in the innate immunity of the skin. It is characterized by the occurrence of nodules, abscesses, fistulas, scars. OBJECTIVE: Although a relationship has already been demonstrated between HS and innate immunity, IGF-1 status in patients with HS is still unknown. The objective of this pilot study was to determine IGF-1 status in patients with HS as well as its potential relationship with the clinical profile of the disease. METHODS: This monocentric and cross-sectional study involved 39 patients hospitalized at the Dermatology Department of CHU Nantes between November 2014 and January 2018. Clinical data and IGF1 status were collected during the follow-up consultation. RESULTS: Forty-nine percent of the patients had very low levels of IGF-1. At the clinical level, these patients were young and with a short duration of disease. The major difference was that IGF1-deficient patients had a higher BMI than others. The others factors differing between the two patient groups did not reach statistical significance. CONCLUSION: This exploratory pilot study indicates that HS with a low level of IGF-1 could represent a specific phenotype of patients with HS. These preliminary results have to be confirmed with a larger cohort, as they could have practical consequences in the therapeutic care of these patients.

Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites.

The use of artemisinin and its derivatives has helped reduce the burden of malaria caused by Plasmodium falciparum. However, artemisinin-resistant parasites are able, in the presence of artemisinins, to stop their cell cycles. This quiescent state can alter the activity of artemisinin partner drugs leading to a secondary drug resistance and thus threatens malaria eradication strategies. Drugs targeting epigenetic mechanisms (namely epidrugs) are emerging as potential antimalarial drugs. Here, we set out to evaluate a selection of various epidrugs for their activity against quiescent parasites, to explore the possibility of using these compounds to counter artemisinin resistance. The 32 chosen epidrugs were first screened for their antiplasmodial activity and selectivity. We then demonstrated, thanks to the specific Quiescent-stage Survival Assay, that four epidrugs targeting both histone methylation or deacetylation as well as DNA methylation decrease the ability of artemisinin-resistant parasites to recover after artemisinin exposure. In the quest for novel antiplasmodial drugs with new modes of action, these results reinforce the therapeutic potential of epidrugs as antiplasmodial drugs especially in the context of artemisinin resistance.

The Immunomodulatory Effects of a 6-Month Extra Virgin Olive Oil Intervention on Monocyte Cytokine Secretion and Plasma Cytokine Levels in Dyslipidemic and Post-Infarct Patients: A Clinical Pilot Study.

Atherosclerosis is an immuno-inflammatory process underlying cardiovascular diseases. One of the main actors of this inflammation is monocytes, with the switch in their phenotypes and irregularities in their cytokine production. OBJECTIVE: This study was aimed to investigate the nutraceutical potential of extra virgin olive oil (EVOO) on the inflammatory status of monocytes in participants showing different levels of cardiovascular risk. METHODS: 43 participants 65-85 years old were recruited including 14 healthy, 12 dyslipidemic patients with hypercholesterolemia recently diagnosed, and 17 post-infarct patients. Participants from all groups were supplemented with EVOO (25 mL/day) for 6 months. IL-1ß, IL-6, IL-10, TNF-α cytokine production, and monocyte phenotypes were investigated both at quiescent and at stimulated state by flow cytometry. RESULTS: At the baseline (pre-intervention), dyslipidemic patients, compared to healthy and post-infarct participants, showed monocytes in an inflammatory state characterized by a significantly weaker IL-10 production. Our results do not show a significant modulation of the phenotype or IL-10, IL-6, and TNF-α production following a 6-month EVOO intake whether at quiescence or under stimulation. However, IL-1ß is significantly increased by the intervention of EVOO in post-infarct patients. Paradoxically after the 6-month intervention, monocytes from dyslipidemic patients showed a significantly decreased secretion of IL-1ß under LPS stimulation despite the increase observed at basal state. CONCLUSION: Our results show that 6-month EVOO intervention did not induce a monocyte phenotypic change or that this intervention significantly modifies cytokine production.

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.

No-reflow after primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction: an angiographic core laboratory analysis of the TOTAL Trial.

BACKGROUND: The optimal strategy to prevent no-reflow in ST-elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI) is unknown. AIMS: We aimed to examine the effect of thrombectomy on the outcome of no-reflow in key subgroups and the adverse clinical outcomes associated with no-reflow. METHODS: We performed a post hoc analysis of the TOTAL Trial, a randomised trial of 10,732 patients comparing thrombectomy versus PCI alone. This analysis utilised the angiographic data of 1,800 randomly selected patients. RESULTS: No-reflow was diagnosed in 196 of 1,800 eligible patients (10.9%). No-reflow occurred in 95/891 (10.7%) patients randomised to thrombectomy compared with 101/909 (11.1%) in the PCI-alone arm (odds ratio [OR] 0.95, 95% confidence interval [CI]: 0.71-1.28; p-value=0.76). In the subgroup of patients who underwent direct stenting, those randomised to thrombectomy compared with PCI alone experienced less no-reflow (19/371 [5.1%] vs 21/216 [9.7%], OR 0.50, 95% CI: 0.26-0.96). In patients who did not undergo direct stenting, there was no difference between the groups (64/504 [12.7%] vs 75/686 [10.9%)], OR 1.18, 95% CI: 0.82-1.69; interaction p-value=0.02). No-reflow patients had a significantly increased risk of experiencing the primary composite outcome (cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA Class IV heart failure) at 1 year (adjusted hazard ratio 1.70, 95% CI: 1.13-2.56; p-value=0.01). CONCLUSIONS: In patients with STEMI treated by PCI, thrombectomy did not reduce no-reflow in all patients but may be synergistic with direct stenting. No-reflow is associated with increased adverse clinical outcomes.

Small Dense LDL Level and LDL/HDL Distribution in Acute Coronary Syndrome Patients.

This study aimed to determine the size and distribution of LDL and HDL particles in North African acute coronary syndrome (ACS) patients and to compare the level of small dense LDL (sdLDL) to other markers used in cardiovascular risk prediction. METHODS: A total of 205 ACS patients and 100 healthy control subjects were enrolled. LDL particle size and LDL and HDL subclass distributions were measured using Quantimetric Lipoprint® linear polyacrylamide gel electrophoresis. Lipid ratios (total cholesterol, LDL cholesterol, non-HDL cholesterol, and HDL cholesterol) were determined to calculate the atherogenic index of plasma (AIP), the atherogenic coefficient (AC), Castelli's Risk-I (CR-I), and Castelli's Risk-II (CR-II). Receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) were used to assess the predictive value of sdLDL as a marker for cardiovascular disease. RESULTS: The ACS patients, compared to the healthy control subjects, displayed an alteration of LDL particle distribution, with a significant increase in sdLDL serum concentrations (0.303 ± 0.478 mmol/L vs. 0.0225 ± 0.043 mmol/L, respectively, p < 0.001). The sdLDL levels had a high discrimination accuracy [AUC = 0.847 ± 0.0353 (95% CI 0.778 to 0.916, p < 0.0001)]. The best predictive cutoff value of ACS determined with the maximum Youden index (J) [(sensitivity + specificity) - 1 = 0.60] was 0.038 mmol/L. A Spearman correlation analysis showed that sdLDL levels were moderately but significantly and positively correlated with AC and CR-I (r = 0.37, p < 0.001) and weakly but significantly correlated with PAI and CR-II; r = 0.32 (p < 0.001) and r = 0.30 (p < 0.008), respectively. The subclass distribution of HDL particles from ACS patients was also altered, with a decrease in large HDL particles and an increase in small HDL particles compared to HDL from healthy control subjects. CONCLUSION: Due to their high atherogenicity, sdLDL levels could be used as a valuable marker for the prediction cardiovascular events.

Race and Ethnicity With Atherosclerotic Cardiovascular Disease Outcomes Within a Universal Health Care System: Insights From the CARTaGENE Study.

BACKGROUND: It remains unclear whether racial and ethnic disparities for atherosclerotic cardiovascular disease (ASCVD) persist within universal health care systems. We aimed to explore long-term ASCVD outcomes within a single-payer health care system with extensive drug coverage in Québec, Canada. METHODS: CARTaGENE (CaG) is a population-based prospective cohort study of individuals aged 40 to 69 years. We included only participants without previous ASCVD. The primary composite endpoint was time to the first ASCVD event (cardiovascular death, acute coronary syndrome, ischemic stroke-transient ischemic attack, or peripheral arterial vascular event). RESULTS: The study cohort included 18,880 participants followed for a median of 6.6 years (2009 to 2016). The mean age was 52 years, and 52.4% were female. After further adjustment for socioeconomic and cardiovascular factors, the increase in ASCVD risk for South Asians (SAs) was attenuated (hazard ratio [HR], 1.41; 95% confidence interval [CI], 0.75, 2.67), whereas Black participants' risk was lower (HR, 0.52; 95% CI, 0.29, 0.95) compared with White participants. After similar adjustments, there were no significant differences in ASCVD outcomes among the Middle Eastern, Hispanic, East-Southeast Asian, Indigenous, and mixed race-ethnicities participants and the White participants. CONCLUSIONS: After adjustment for CV risk factors, the risk of ASCVD was attenuated in the SA CaG participants. Intensive risk-factor modification may mitigate the ASCVD risk of the SAs. Within a universal health care context and comprehensive drug coverage, the ASCVD risk was lower among Black compared with White CaG participants. Future studies are needed to confirm whether universal and liberal access to health care and medications can reduce the rates of ASCVD among the Black population.

Non-calcified active atherosclerosis plaque detection with 18F-NaF and 18F-FDG PET/CT dynamic imaging.

Arterial inflammation is an indicator of atheromatous plaque vulnerability to detach and to obstruct blood vessels in the heart or in the brain thus causing heart attack or stroke. To date, it is difficult to predict the plaque vulnerability. This study was aimed to assess the behavior of 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake in the aorta and iliac arteries as a function of plaque density on CT images. We report metabolically active artery plaques associated to inflammation in the absence of calcification. 18 elderly volunteers were recruited and imaged with computed tomography (CT) and positron emission tomography (PET) with 18F-NaF and 18F-FDG. A total of 1338 arterial segments were analyzed, 766 were non-calcified and 572 had calcifications. For both 18F-NaF and 18F-FDG, the mean SUV values were found statistically significantly different between non-calcified and calcified artery segments. Clustering CT non-calcified segments, excluding blood, resulted in two clusters C1 and C2 with a mean density of 30.63 ± 5.06 HU in C1 and 43.06 ± 4.71 HU in C2 (P < 0.05), and their respective SUV were found statistically different in 18F-NaF and 18F-FDG. The 18F-NaF images showed plaques not detected on CT images, where the 18F-FDG SUV values were high in comparison to artery walls without plaques. The density on CT images alone corresponding to these plaques could be further investigated to see whether it can be an indicator of the active plaques.

Older patients with COVID-19 and neuropsychiatric conditions: A study of risk factors for mortality.

BACKGROUND: Little is known about risk factors for mortality in older patients with COVID-19 and neuropsychiatric conditions. METHODS: We conducted a multicentric retrospective observational study at Assistance Publique-Hôpitaux de Paris. We selected inpatients aged 70 years or older, with COVID-19 and preexisting neuropsychiatric comorbidities and/or new neuropsychiatric manifestations. We examined demographics, comorbidities, functional status, and presentation including neuropsychiatric symptoms and disorders, as well as paraclinical data. Cox survival analysis was conducted to determine risk factors for mortality at 40 days after the first symptoms of COVID-19. RESULTS: Out of 191 patients included (median age 80 [interquartile range 74-87]), 135 (71%) had neuropsychiatric comorbidities including cognitive impairment (39%), cerebrovascular disease (22%), Parkinsonism (6%), and brain tumors (6%). A total of 152 (79%) patients presented new-onset neuropsychiatric manifestations including sensory symptoms (6%), motor deficit (11%), behavioral (18%) and cognitive (23%) disturbances, gait impairment (11%), and impaired consciousness (18%). The mortality rate at 40 days was 19.4%. A history of brain tumor or Parkinsonism or the occurrence of impaired consciousness were neurological factors associated with a higher risk of mortality. A lower Activities of Daily Living score (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.58-0.82), a neutrophil-to-lymphocyte ratio ≥ 9.9 (HR 5.69, 95% CI 2.69-12.0), and thrombocytopenia (HR 5.70, 95% CI 2.75-11.8) independently increased the risk of mortality (all p < .001). CONCLUSION: Understanding mortality risk factors in older inpatients with COVID-19 and neuropsychiatric conditions may be helpful to neurologists and geriatricians who manage these patients in clinical practice.

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides.

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 µM) and M. tuberculosis (MIC = 9 µM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 µM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions.

Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules.

The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC50 =622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 µm indicating a specific antiplasmodial mode of action.

Prognostic value of electroencephalographic paroxysms in post-anoxic coma: A new regularity EEG-based score.

OBJECTIVES: Several electroencephalographic (EEG) features -mainly the reactivity of background activity-have been suggested as reliable predictors of outcome for patients with post-anoxic coma (PAC). However, EEG in PAC often contains abundant EEG paroxysms (EP) that may hinder the detection of background EEG activity. We aimed to identify the features, among the different paroxysmal and non-paroxysmal EEG patterns, that may predict the outcome of patients with PAC. METHODS: We retrospectively reviewed the clinical and EEG characteristics of 67 patients with PAC and selected those with abundant EP. We classified EP according to several features and assessed their prognostic value for survival at 15 days. We calculated a global regularity score, as the sum of the value (1 if regular, 0 if not) attributed to each of 4 features of EP (duration, morphology, amplitude, and frequency). RESULTS: The 35 patient-group with abundant EP showed a higher mortality than the group without abundant EP. Among 12 features of EP, four regularity features (regularity of EP duration, morphology, amplitude, and global regularity score) had a poor prognostic value. A global regularity score ≥ 3 showed a positive predictive value of 100 % for a poor outcome and a negative predictive value of 54 %, with good interrater consistency (Cohen's kappa = .63). CONCLUSIONS: The presence of EP and their regularity features in PAC patients are strongly associated with poor outcome. We propose a global regularity score, easily derived from visual EEG inspection, that may be a reliable prognostic tool for these patients. Prospective and larger studies are needed to confirm these findings.

The effect of diabetes on surgical versus percutaneous left main revascularization outcomes: a systematic review and meta-analysis.

BACKGROUND: The optimal method of coronary revascularization for diabetes mellitus (DM) patients with left main coronary artery disease (LMCAD) is controversial in the drug-eluting stent (DES) era. METHODS: We performed a systematic review and meta-analysis comparing DES-based percutaneous coronary intervention (PCI) to coronary artery bypass grafting (CABG) for LMCAD in DM patients and tested for effect measure modification (EMM) by diabetes for adverse events. We included all randomized controlled trials (RCTs) and observational studies comparing CABG to DES-based PCI including DM patients with LMCAD published up to March 1, 2021. We completed separate random-effects meta-analyses for four RCTs (4356 patients, mean follow-up of 4.9 years) and six observational studies (9360 patients, mean follow-up of 5.2 years). RESULTS: In RCTs among DM patients, DES-based PCI, compared to CABG, was associated with a 30% increased relative risk (RR) (RR 1.30, 95% CI 1.09-1.56, I2 = 0%), while among non-DM patients, there was a 25% increased relative risk (RR 1.25, 95% CI 1.07-1.44, I2 = 0%) for the composite endpoint of all-cause mortality, myocardial infarction, stroke, and unplanned revascularization (MACCE). There was no evidence of EMM (p-value for interaction = 0.70). The mean weighted SYNTAX score was 25.7. In observational studies, there was no difference between DES-based PCI and CABG for all-cause mortality in patients with DM (RR 1.13, 95% CI 0.91-1.40, I2 = 0%). CONCLUSIONS: CABG was superior to PCI for LMCAD in RCTs in DM patients for MACCE. Heart teams may consider DM as one of the many components in the clinical decision-making process, but may not want to consider DM as a primary deciding factor between DES-based PCI and CABG for LMCAD with low to intermediate anatomical complexity in the other coronary arteries. STUDY REGISTRATION: CRD42021246931 (PROSPERO).

Epilepsy related to focal neuronal lipofuscinosis: extra-frontal localization, EEG signatures and GABA involvement.

Focal neuronal lipofuscinosis (FNL) is an uncommon epileptic disorder related to an excess of lipofuscin accumulation within dysmorphic-appearing neurons (DANs), whose epileptogenic mechanisms are still poorly understood. It shares some clinical and neuroimaging similarities with focal cortical dysplasia of type IIb (FCDIIb), but it represents a different pathological entity. Here, we identified two patients with FNL among a 10-year cohort of 323 patients who underwent neurosurgery for a focal pharmacoresistant epilepsy. We describe the electroclinical, metabolic and neuropathological features of both patients with FNL who benefited from a comprehensive presurgical investigation. While the previous reports showed frontal lobe localization of the lesion, FNL was identified in the temporal lobe, in one of our patients. EEG investigations in both patients showed striking focal and rich interictal activity resembling that described in FCDIIb. Besides focal intraneuronal lipofuscin accumulation, the neuropathological analysis demonstrated that somata of DANs were surrounded by a large amount of GABAergic presynaptic buttons, suggesting the involvement of interneurons in the epileptogenicity of FNL. To further explore the role of GABAergic transmission in the generation of epileptiform activity in FNL, we performed in vitro multi-electrode array recordings on the post-surgery tissue from one patient. Spontaneous interictal-like discharges (IILDs) were identified only in the restricted area displaying the highest density of lipofuscin-containing DANs, suggesting a close correlation between the density of lipofuscin-containing neurons and epileptogenicity. Moreover, IILDs were blocked by the GABAA receptor antagonist gabazine. All together, these findings showed how GABA signaling may contribute to the generation of interictal-like activity in FNL tissue.

Serum neuron-specific enolase: a new tool for seizure risk monitoring after status epilepticus.

BACKGROUND AND PURPOSE: There is a need for accurate biomarkers to monitor electroencephalography (EEG) activity and assess seizure risk in patients with acute brain injury. Seizure recurrence may lead to cellular alterations and subsequent neurological sequelae. Whether neuron-specific enolase (NSE) and S100-beta (S100B), brain injury biomarkers, can reflect EEG activity and help to evaluate the seizure risk was investigated. METHODS: Eleven patients, admitted to an intensive care unit for refractory status epilepticus, who underwent a minimum of 3 days of continuous EEG concomitantly with daily serum NSE and S100B assays were included. At 103 days the relationships between serum NSE and S100B levels and two EEG scores able to monitor the seizure risk were investigated. Biochemical biomarker thresholds able to predict seizure recurrence were sought. RESULTS: Only NSE levels positively correlated with EEG scores. Similar temporal dynamics were observed for the time courses of EEG scores and NSE levels. NSE levels above 17 ng/ml were associated with seizure in 71% of patients. An increase of more than 15% of NSE levels was associated with seizure recurrence in 80% of patients. CONCLUSIONS: Our study highlights the potential of NSE as a biomarker of EEG activity and to assess the risk of seizure recurrence.

A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites.

Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease via the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity. One molecule, named gamhepathiopine (denoted as "M1" herein), was active at submicromolar concentrations against both erythrocytic (50% effective concentration [EC50] = 0.045 µM) and liver (EC50 = 0.45 µM) forms of Plasmodium falciparum. Furthermore, gamhepathiopine efficiently blocked the development of the sporogonic cycle in the mosquito vector by inhibiting the exflagellation step. Moreover, M1 was active against artemisinin-resistant forms (EC50 = 0.227 µM), especially at the quiescent stage. Nevertheless, in mice, M1 showed modest activity due to its rapid metabolization by P450 cytochromes into inactive derivatives, calling for the development of new parent compounds with improved metabolic stability and longer half-lives. These results highlight the thienopyrimidinone scaffold as a novel antiplasmodial chemotype of great interest to search for new drug candidates displaying multistage activity and an original mechanism of action with the potential to be used in combination therapies for malaria elimination in the context of artemisinin resistance. IMPORTANCE This work reports a new chemical structure that (i) displays activity against the human malaria parasite Plasmodium falciparum at 3 stages of the parasitic cycle (blood stage, hepatic stage, and sexual stages), (ii) remains active against parasites that are resistant to the first-line treatment recommended by the World Health Organization (WHO) for the treatment of severe malaria (artemisinins), and (iii) reduces transmission of the parasite to the mosquito vector in a mouse model. This new molecule family could open the way to the conception of novel antimalarial drugs with an original multistage mechanism of action to fight against Plasmodium drug resistance and block interhuman transmission of malaria.

Seizures in autoimmune encephalitis: specific features based on a systematic comparative study.

OBJECTIVE: To highlight specific characteristics of seizure semiology and EEG features associated with different subtypes of autoimmune encephalitis (AE). METHODS: We systematically reviewed the seizure semiology and all the EEG recordings from patients with AE managed in a tertiary referral centre for epilepsy and a neuro-intensive care unit. Each characteristic across the different subtypes of AE was compared by post hoc analysis. RESULTS: We identified 66 patients with anti-neuronal antibody-mediated AE or Rasmussen's encephalitis (RE) experiencing seizures, which were the most frequent symptom at onset. Anti-NMDAR and anti-LGI1 AE accounted for the majority of patients; 41% and 24%, respectively. We isolated specific semiological features, such as early tonic-clonic seizures (TCS) in anti-NMDAR AE, early mesial temporal lobe seizures with emotional symptoms in anti-GAD AE, somatosensory seizures in RE, and a lower frequency of TCS in anti-LGI1 AE. EEG analysis also provided additional insights into distinguishing the subtypes based on: (1) generalized rhythmic delta activity, which was more sensitive than extreme delta brush in identifying anti-NMDAR AE among all subtypes; and (2) temporal interictal epileptiform activity and temporal seizures on EEG in anti-GAD AE. We identified a new EEG pattern consisting of temporal low-voltage and periodic spikes associated with ipsilateral hippocampal abnormalities on MRI, which could be a sign of inflammatory mesial temporal involvement. SIGNIFICANCE: Specific clinical and EEG features can be useful in guiding the diagnosis of a subtype of AE with acute symptomatic seizures, particularly before the results of anti-neuronal antibody testing are available.