Simultaneous measurement of orthogonal terahertz fields via an emission multiplexing scheme.

We propose a polarization sensitive terahertz time-domain spectrometer that can record orthogonally polarized terahertz fields simultaneously, using fibre-coupled photoconductive antennas and a scheme that modulated the emitter's polarization. The s and p channels of the multi-pixel terahertz emitter were modulated at different frequencies, thereby allowing orthogonal waveforms to be demultiplexed from the recorded signal in post-processing. The performance of the multi-pixel emitter used in this multiplexing scheme was comparable to that of a commercial single-polarization H-dipole antenna. The approach allowed two orthogonally polarized terahertz pulses to be recorded with good signal to noise (>1000:1) within half a second. We verified the capability of the spectrometer by characterizing a birefringent crystal and by imaging a polarization-sensitive metamaterial. This work has significant potential to improve the speed of terahertz polarization sensitive applications, such as ellipsometry and imaging.

Testing drivers of acoustic divergence in cicadas (Cicadidae: Tettigettalna).

Divergence in acoustic signals may have a crucial role in the speciation process of animals that rely on sound for intra-specific recognition and mate attraction. The acoustic adaptation hypothesis (AAH) postulates that signals should diverge according to the physical properties of the signalling environment. To be efficient, signals should maximize transmission and decrease degradation. To test which drivers of divergence exert the most influence in a speciose group of insects, we used a phylogenetic approach to the evolution of acoustic signals in the cicada genus Tettigettalna, investigating the relationship between acoustic traits (and their mode of evolution) and body size, climate and micro-/macro-habitat usage. Different traits showed different evolutionary paths. While acoustic divergence was generally independent of phylogenetic history, some temporal variables' divergence was associated with genetic drift. We found support for ecological adaptation at the temporal but not the spectral level. Temporal patterns are correlated with micro- and macro-habitat usage and temperature stochasticity in ways that run against the AAH predictions, degrading signals more easily. These traits are likely to have evolved as an anti-predator strategy in conspicuous environments and low-density populations. Our results support a role of ecological selection, not excluding a likely role of sexual selection in the evolution of Tettigettalna calling songs, which should be further investigated in an integrative approach.

The efficacy and safety of direct oral anticoagulants plus aspirin in symptomatic lower extremity peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials.

Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse limb events (MALE). The efficacy and safety of direct oral anticoagulants (DOACs) in this context is evolving. To assess the efficacy and safety of DOAC combined with aspirin compared to the use of antiplatelet agents in patients with symptomatic lower extremity (LE) PAD. We systematically searched PubMed, Embase and Cochrane databases, in September 2020, for randomized controlled trials (RCTs) that were designed to investigate the effect of DOACs in the treatment of PAD. A random-effects meta-analysis was performed targeting ischemic and bleeding events. Three randomized clinical trials were included, providing a total of 9533 patients, and 744 pooled MALE events (316 in DOAC plus aspirin and 428 in control). Only data on rivaroxaban and edoxaban were available. The use of DOAC plus aspirin in PAD patients significantly decreased the rate of MALE (pooled OR 0.70 [0.61-0.83], P < 0.001; I2 = 0%). In terms of safety, there was a significantly higher rate of major bleeding events (pooled OR 1.46 [1.16-1.84], P = 0.001; I2 = 52%). In rivaroxaban-RCTs, the addition of low-dose rivaroxaban to aspirin was still associated with a lower MALE compared to aspirin alone (pooled OR 0.68 [0.53-0.88], P = 0.003; I2 = 28%), but also conferred higher major bleeding rate (pooled OR 1.48 [1.18-1.86], P < 0.001; I2 = 0%). In conclusion, our pooled data suggests that for patients with symptomatic LE-PAD, the use of DOAC combined with aspirin reduced the risk of major ischemic limb events at the expense of an increased risk of major bleeding.

Use of a physiologically-based pharmacokinetic model to explore the potential disparity in nicotine disposition between adult and adolescent nonhuman primates.

The widespread use and high abuse liability of tobacco products has received considerable public health attention, in particular for youth, who are vulnerable to nicotine addiction. In this study, adult and adolescent squirrel monkeys were used to evaluate age-related metabolism and pharmacokinetics of nicotine after intravenous administration. A physiologically-based pharmacokinetic (PBPK) model was created to characterize the pharmacokinetic behaviors of nicotine and its metabolites, cotinine, trans-3'-hydroxycotinine (3'-OH cotinine), and trans-3'-hydroxycotinine glucuronide (3'-OH cotinine glucuronide) for both adult and adolescent squirrel monkeys. The PBPK nicotine model was first calibrated for adult squirrel monkeys utilizing in vitro nicotine metabolic data, plasma concentration-time profiles and cumulative urinary excretion data for nicotine and metabolites. Further model refinement was conducted when the calibrated adult model was scaled to the adolescents, because adolescents appeared to clear nicotine and cotinine more rapidly relative to adults. More specifically, the resultant model parameters representing systemic clearance of nicotine and cotinine for adolescent monkeys were approximately two- to three-fold of the adult values on a per body weight basis. The nonhuman primate PBPK model in general captured experimental observations that were used for both model calibration and evaluation, with acceptable performance metrics for precision and bias. The model also identified differences in nicotine pharmacokinetics between adolescent and adult nonhuman primates which might also be present in humans.

Mutagenicity of acrylamide and glycidamide in human TP53 knock-in (Hupki) mouse embryo fibroblasts.

Acrylamide is a suspected human carcinogen formed during high-temperature cooking of starch-rich foods. It is metabolised by cytochrome P450 2E1 to its reactive metabolite glycidamide, which forms pre-mutagenic DNA adducts. Using the human TP53 knock-in (Hupki) mouse embryo fibroblasts (HUFs) immortalisation assay (HIMA), acrylamide- and glycidamide-induced mutagenesis was studied in the tumour suppressor gene TP53. Selected immortalised HUF clones were also subjected to next-generation sequencing to determine mutations across the whole genome. The TP53-mutant frequency after glycidamide exposure (1.1 mM for 24 h, n = 198) was 9% compared with 0% in cultures treated with acrylamide [1.5 (n = 24) or 3 mM (n = 6) for 48 h] and untreated vehicle (water) controls (n = 36). Most glycidamide-induced mutations occurred at adenines with A > T/T > A and A > G/T > C mutations being the most common types. Mutations induced by glycidamide occurred at specific TP53 codons that have also been found to be mutated in human tumours (i.e., breast, ovary, colorectal, and lung) previously associated with acrylamide exposure. The spectrum of TP53 mutations was further reflected by the mutations detected by whole-genome sequencing (WGS) and a distinct WGS mutational signature was found in HUF clones treated with glycidamide that was again characterised by A > G/T > C and A > T/T > A mutations. The WGS mutational signature showed similarities with COSMIC mutational signatures SBS3 and 25 previously found in human tumours (e.g., breast and ovary), while the adenine component was similar to COSMIC SBS4 found mostly in smokers' lung cancer. In contrast, in acrylamide-treated HUF clones, only culture-related background WGS mutational signatures were observed. In summary, the results of the present study suggest that glycidamide may be involved in the development of breast, ovarian, and lung cancer.

Pharmacokinetics of oseltamivir phosphate and oseltamivir carboxylate in non-pregnant and pregnant rhesus monkeys.

Oseltamivir is an antiviral drug approved to treat influenza in humans. Although the dosing regimen of this drug is well established for non-pregnant patients, it is not clear if the significant physiological alterations associated with pregnancy affect the pharmacokinetics of oseltamivir and, thus, warrant different dosing regimens to assure efficacy. In this study, we investigated the suitability of rhesus macaques as an animal model for studying oseltamivir pharmacokinetics during all trimesters of pregnancy in comparison to pre-pregnant conditions. Specifically, we compared the pharmacokinetics of oseltamivir and its pharmacologically active metabolite oseltamivir carboxylate in rhesus monkeys after intravenous and nasogastric administration of 2.5 mg oseltamivir phosphate/kg body weight given prior to and during the first, second, and third trimesters of pregnancy. Pregnancy had only a modest effect upon the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate. Monkeys treated intravenously in the third trimester had a reduction in Vd and CL, compared to non-pregnant monkeys. These changes did not occur in the other two trimesters. Pregnant monkeys treated intravenously had 20-25% decrease in AUC0-∞ of oseltamivir carboxylate and a corresponding increase in Vd and CL. Pregnant monkeys treated nasogastrically with oseltamivir phosphate demonstrated a pattern that recapitulated intravenous dosing. Taken together these data indicate that rhesus monkeys are an acceptable model for studying drug-pregnancy interactions.

1-Formyl-7-hydroxy-6,7-dihydro-5 H-pyrrolizine (1-CHO-DHP): A Potential Proximate Carcinogenic Metabolite of Pyrrolizidine Alkaloids.

Pyrrolizidine alkaloids (PAs) are phytochemicals present in more than 6000 plant species worldwide; about half of the PAs are hepatotoxic, genotoxic, and carcinogenic. Because of their wide exposure and carcinogenicity, the International Programme on Chemical Safety (IPCS) concluded that PAs are a threat to human health and safety. We recently determined that PA-induced liver tumor initiation is mediated by a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-pyrrolizine (DHP)-DNA adducts and proposed that these DHP-DNA adducts are biomarkers of PA exposure and liver tumor initiation. To validate the generality of this metabolic activation pathway and DHP-DNA adducts as biomarkers, it is significant to identify reactive metabolites associated with this metabolic activation pathway. Segall et al. ( Segall et al. ( 1984 ) Drug Metab. Dispos. 12 , 68 - 71 ) previously reported that 1-formyl-7-hydroxy-6,7-dihydro-5 H-pyrrolizine (1-CHO-DHP) is generated from the metabolism of senecionine by mouse liver microsomes. In the present study, we examined the metabolism of seven hepatocarcinogenic PAs (senecionine, intermedine, retrorsine, riddelliine, DHR, heliotrine, and senkirkine) and one noncarcinogenic PA (platyphylline) by human, rat, and mouse liver microsomes. 1-CHO-DHP was identified as a common metabolite from the metabolism of these hepatotoxic PAs, but not from platyphylline. Incubation of 1-CHO-DHP with HepG2 and A549 cells produced the same set of DHP-DNA adducts, which were identified by both LC/MS MRM mode and selected ion monitoring analyses through comparison to synthetic standards. In the incubation medium of 1-CHO-DHP treated HepG2 cells, both DHP and 7-cysteine-DHP were formed, which were capable of binding to cellular DNA to produce DHP-DNA adducts. These results suggest that 1-CHO-DHP is a proximate DNA metabolite of genotoxic and carcinogenic PAs.

Cytochrome P450-mediated metabolism of triclosan attenuates its cytotoxicity in hepatic cells.

Triclosan is a widely used broad-spectrum anti-bacterial agent. The objectives of this study were to identify which cytochrome P450 (CYP) isoforms metabolize triclosan and to examine the effects of CYP-mediated metabolism on triclosan-induced cytotoxicity. A panel of HepG2-derived cell lines was established, each of which overexpressed a single CYP isoform, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1. The extent of triclosan metabolism by each CYP was assessed by reversed-phase high-performance liquid chromatography with online radiochemical detection. Seven isoforms were capable of metabolizing triclosan, with the order of activity being CYP1A2 > CYP2B6 > CYP2C19 > CYP2D6 ≈ CYP1B1 > CYP2C18 ≈ CYP1A1. The remaining 11 isoforms (CYP2A6, CYP2A7, CYP2A13, CYP2C8, CYP2C9, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1) had little or no activity toward triclosan. Three metabolites were detected: 2,4-dichlorophenol, 4-chlorocatechol, and 5'-hydroxytriclosan. Consistent with the in vitro screening data, triclosan was extensively metabolized in HepG2 cells overexpressing CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP2C18, and these cells were much more resistant to triclosan-induced cytotoxicity compared to vector cells, suggesting that CYP-mediated metabolism of triclosan attenuated its cytotoxicity. In addition, 2,4-dichlorophenol and 4-chlorocatechol were less toxic than triclosan to HepG2/vector cells. Conjugation of triclosan, catalyzed by human glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), also occurred in HepG2/CYP-overexpressing cells and primary human hepatocytes, with a greater extent of conjugation being associated with higher cell viability. Co-administration of triclosan with UGT or SULT inhibitors led to greater cytotoxicity in HepG2 cells and primary human hepatocytes, indicating that glucuronidation and sulfonation of triclosan are detoxification pathways. Among the 18 CYP-overexpressing cell lines, an inverse correlation was observed between cell viability and the level of triclosan in the culture medium. In conclusion, human CYP isoforms that metabolize triclosan were identified, and the metabolism of triclosan by CYPs, UGTs, and SULTs decreased its cytotoxicity in hepatic cells.

The role of fibrinogen glycation in ATTR: evidence for chaperone activity loss in disease.

Transthyretin amyloidosis (ATTR) belongs to a class of disorders caused by protein misfolding and aggregation. ATTR is a disabling disorder of autosomal dominant trait, where transthyretin (TTR) forms amyloid deposits in different organs, causing dysfunction of the peripheral nervous system. We previously discovered that amyloid fibrils from ATTR patients are glycated by methylglyoxal. Even though no consensus has been reached about the actual role of methylglyoxal-derived advanced glycation end-products in amyloid diseases, evidence collected so far points to a role for protein glycation in conformational abnormalities, being ubiquitously found in amyloid deposits in Alzheimer's disease, dialysis-related amyloidosis and Parkinson's diseases. Human fibrinogen, an extracellular chaperone, was reported to specifically interact with a wide spectrum of stressed proteins and suppress their aggregation, being an interacting protein with TTR. Fibrinogen is differentially glycated in ATTR, leading to its chaperone activity loss. Here we show the existence of a proteostasis imbalance in ATTR linked to fibrinogen glycation by methylglyoxal.

Metabolic activation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and DNA adduct formation depends on p53: Studies in Trp53(+/+),Trp53(+/-) and Trp53(-/-) mice.

The expression of the tumor suppressor p53 can influence the bioactivation of, and DNA damage induced by, the environmental carcinogen benzo[a]pyrene, indicating a role for p53 in its cytochrome P450 (CYP)-mediated biotransformation. The carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which is formed during the cooking of food, is also metabolically activated by CYP enzymes, particularly CYP1A2. We investigated the potential role of p53 in PhIP metabolism in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with a single oral dose of 50 mg/kg body weight PhIP. N-(Deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP-C8-dG) levels in DNA, measured by liquid chromatography-tandem mass spectrometry, were significantly lower in liver, colon, forestomach and glandular stomach of Trp53(-/-) mice compared to Trp53(+/+) mice. Lower PhIP-DNA adduct levels in the livers of Trp53(-/-) mice correlated with lower Cyp1a2 enzyme activity (measured by methoxyresorufin-O-demethylase activity) in these animals. Interestingly, PhIP-DNA adduct levels were significantly higher in kidney and bladder of Trp53(-/-) mice compared to Trp53(+/+) mice, which was accompanied by higher sulfotransferase (Sult) 1a1 protein levels and increased Sult1a1 enzyme activity (measured by 2-naphthylsulfate formation from 2-naphthol) in kidneys of these animals. Our study demonstrates a role for p53 in the metabolism of PhIP in vivo, extending previous results on a novel role for p53 in xenobiotic metabolism. Our results also indicate that the impact of p53 on PhIP biotransformation is tissue-dependent and that in addition to Cyp1a enzymes, Sult1a1 can contribute to PhIP-DNA adduct formation.

Characterization of water-soluble organic matter in urban aerosol by 1H-NMR spectroscopy.

The functional and 13C isotopic compositions of water-soluble organic carbon (WSOC) in atmospheric aerosol were determined by nuclear magnetic resonance (1H-NMR) and isotope ratio mass spectrometry (IRMS) in an urban location in the Southern Mississippi Valley. The origin of WSOC was resolved using the functional distribution of organic hydrogen, δ13C ratio, and positive matrix factorization (PMF). Three factors were retained based on NMR spectral bins loadings. Two factors (factors 1 and 3) demonstrated strong associations with the aliphatic region in the NMR spectra and levoglucosan resonances. Differences between the two factors included the abundance of the aromatic functional group for factor 1, indicating fresh emissions and, for factor 3, the presence of resonances attributed to secondary ammonium nitrate and low δ13C ratio values that are indicative of secondary organic aerosol. Factors 1 and 3 added 0.89 and 1.08 µgC m-3, respectively, with the highest contribution in the summer and fall. Factor 2 retained resonances consistent with saccharides and was attributed to pollen particles. Its contribution to WSOC varied from 0.22 µgC m-3 in winter to 1.04 µgC m-3 in spring.

Absorption and metabolism of triclosan after application to the skin of B6C3F1 mice.

Triclosan is used as an antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Humans can receive lifelong exposures to triclosan; however, data on the toxicity and carcinogenicity after topical application are lacking. This study determined the absorption, distribution, metabolism, and excretion of triclosan after application to the skin of B6C3F1 mice. [(14)C(U)]triclosan (10 or 100 mg triclosan/kg body weight) was administered topically to mice in two separate experiments: a vehicle selection experiment using propylene glycol, ethanol, and a generic cosmetic cream, and a toxicokinetic experiment. Mice were killed up to 72 h after triclosan administration, and excreta and tissues were analyzed for radioactivity. Ethanol had the best properties of the vehicles evaluated. Maximum absorption was obtained at approximately 12 h after dosing. Radioactivity appeared in the excreta and in all tissues examined, with the highest levels in the gall bladder and the lowest levels in the brain. Triclosan was metabolized to triclosan sulfate, triclosan glucuronide, 2,4-dichlorophenol, and hydroxytriclosan. The metabolite profile was tissue-dependent and the predominant route of excretion was fecal. The AUC(0-∞) and the Cmax of plasma and liver in females were greater than those in males. Slightly lower absorption was observed in mice with Elizabethan collars.

Exceptionally long-term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients with aristolochic acid nephropathy.

Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography 32P-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy.

Reaction of dehydropyrrolizidine alkaloids with valine and hemoglobin.

Pyrrolizidine alkaloid-containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids exert toxicity through metabolism to dehydropyrrolizidine alkaloids that bind to cellular protein and DNA, leading to hepatotoxicity, genotoxicity, and tumorigenicity. To date, it is not clear how dehydropyrrolizidine alkaloids bind to cellular constituents, including amino acids and proteins, resulting in toxicity. Metabolism of carcinogenic monocrotaline, riddelliine, and heliotrine produces dehydromonocrotaline, dehyroriddelliine, and dehydroheliotrine, respectively, as primary reactive metabolites. In this study, we report that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived valine (DHP-valine) adducts. For structural elucidation, DHP-valine adducts were derivatized with phenyl isothiocyanate (PITC) to DHP-valine-PITC products. After HPLC separation, their structures were characterized by mass spectrometry, UV-visible spectrophotometry, (1)H NMR, and (1)H-(1)H COSY NMR spectral analysis. Two DHP-valine-PITC adducts, designated as DHP-valine-PITC-1 and DHP-valine-PITC-3, had the amino group of valine linked to the C7 position of the necine base, and the other two DHP-valine-PITC products, DHP-valine-PITC-2 and DHP-valine-PITC-4, linked to the C9 position of the necine base. DHP-valine-PITC-1 was interconvertible with DHP-valine-PITC-3, and DHP-valine-PITC-2 was interconvertible with DHP-valine-PITC-4. Reaction of dehydroriddelliine and dehydroheliotrine with valine provided similar results. However, reaction of valine and dehydroretronecine (DHR) under similar experimental conditions did not produce DHP-valine adducts. Reaction of dehydromonocrotaline with rat hemoglobin followed by derivatization with PITC also generated the same four DHP-valine-PITC adducts. This represents the first full structural elucidation of protein conjugated pyrrolic adducts formed from reaction of dehydropyrrolizidine alkaloids with an amino acid (valine). In addition, it was found that DHP-valine-2 and DHP-valine-4, with the valine amino group linked at the C7 position of the necine base, can lose the valine moiety to form DHP.

Comparison between epileptic seizure prediction and forecasting based on machine learning.

Epilepsy affects around 1% of the population worldwide. Anti-epileptic drugs are an excellent option for controlling seizure occurrence but do not work for around one-third of patients. Warning devices employing seizure prediction or forecasting algorithms could bring patients new-found comfort and quality of life. These algorithms would attempt to detect a seizure's preictal period, a transitional moment between regular brain activity and the seizure, and relay this information to the user. Over the years, many seizure prediction studies using Electroencephalogram-based methodologies have been developed, triggering an alarm when detecting the preictal period. Recent studies have suggested a shift in view from prediction to forecasting. Seizure forecasting takes a probabilistic approach to the problem in question instead of the crisp approach of seizure prediction. In this field of study, the triggered alarm to symbolize the detection of a preictal period is substituted by a constant risk assessment analysis. The present work aims to explore methodologies capable of seizure forecasting and establish a comparison with seizure prediction results. Using 40 patients from the EPILEPSIAE database, we developed several patient-specific prediction and forecasting algorithms with different classifiers (a Logistic Regression, a 15 Support Vector Machines ensemble, and a 15 Shallow Neural Networks ensemble). Results show an increase of the seizure sensitivity in forecasting relative to prediction of up to 146% and in the number of patients that displayed an improvement over chance of up to 300%. These results suggest that a seizure forecasting methodology may be more suitable for seizure warning devices than a seizure prediction one.

Coronary angiography after out-of-hospital cardiac arrest without ST-segment elevation: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) has a poor prognosis. The optimal timing and role of early coronary angiography (CAG) in OHCA patients without ST-segment elevation remains unclear. The goal of this study is to compare an early CAG versus delayed CAG strategy in OHCA patients without ST elevation. METHODS: We systematically searched PubMed, Embase and Cochrane databases, in June 2022, for randomised controlled trials (RCTs) comparing early versus delayed early CAG. A random effects meta-analysis was performed. RESULTS: A total of seven RCTs were included, providing a total of 1625 patients: 816 in an early strategy and 807 in a delayed strategy. In terms of outcomes assessed, our meta-analysis revealed a similar rate of all-cause mortality (pooled odds ratio [OR] 1.22 [0.99-1.50], P  = 0.06, I 2  = 0%), neurological status (pooled OR 0.94 [0.74-1.21], = 0.65, I 2  = 0%), need of renal replacement therapy (pooled OR 1.11 [0.78-1.74], P  = 0.47, I 2  = 0%) and major bleeding events (pooled OR 1.51 [0.95-2.40], P  = 0.08, I 2  = 69%). CONCLUSION: According to our meta-analysis, in patients who experienced OHCA without ST elevation, early CAG is not associated with reduced mortality or an improved neurological status.

Effect of transdermal drug delivery patches on the stratum corneum: in vivo inspection with a handheld terahertz probe.

Transdermal drug delivery patches are a good alternative to hypodermic drug injection. The drug delivery efficiency depends strongly on the hydration of the skin under treatment, and therefore, it is essential to study the effects on the skin induced by the application of these medical-grade patches. Terahertz (THz) spectroscopy shows great promise for non-invasive skin evaluation due to its high sensitivity to subtle changes in water content, low power and non-ionizing properties. In this work, we study the effects of transdermal drug delivery patches (three fully occlusive and three partially occlusive) applied on the upper arms of ten volunteers for a maximum period of 28 h. Three different levels of propylene glycol (0 %, 3 % and 6 %) are added to the patches as excipient. By performing multilayer analysis, we successfully retrieve the water content of the stratum corneum (SC) which is the outermost layer of skin, as well as its thickness at different times before and after applying the patches. This study demonstrates the potential of using THz sensing for non invasive skin monitoring and has wide applications for skin evaluation as well as the development of skin products.

Left atrial appendage occlusion for recurrent stroke while on oral anticoagulation: a case series.

Background: Clinical practice guidelines recommend oral anticoagulation (OAC) for stroke prevention in selected patients with atrial fibrillation (AF). However, some patients still experience thrombo-embolic events despite adequate anticoagulation. The optimal management of these cases remains uncertain, leading to practice pattern variability. We present a series of three cases illustrating the use of left atrial appendage occlusion (LAAO) as an adjunctive stroke prevention strategy in AF patients with recurrent thrombo-embolic events despite adequate anticoagulation. Case summary: Case one describes an 89-year-old female on apixaban who presented with a thrombus and underwent successful mechanical thrombectomy. Left atrial appendage occlusion was performed, and no subsequent thrombo-embolic events were reported. Case 2 involves a 72-year-old female on full-dose apixaban who experienced recurrent strokes despite adequate anticoagulation. Thrombectomy was performed twice, and complications arose during LAAO. The patient was discharged on warfarin + clopidogrel and remained event-free at the six-month follow-up. Case 3 features an 88-year-old female on rivaroxaban who experienced recurrent cerebral ischaemic events and gastrointestinal bleeding. Left atrial appendage occlusion using an Amplatzer Amulet™ device was successful, and the patient remained event-free at the one-year follow-up. Discussion: This case series emphasizes the complexity of stroke prevention in AF patients and underscores the need for an individualized approach. Incorporating LAAO alongside OAC can provide additional stroke protection for patients with inadequate response to anticoagulation. Further randomized controlled trials are needed to evaluate the efficacy and safety of this approach. In light of the limited evidence available, these cases contribute to the growing body of knowledge on the potential role of LAAO in secondary stroke prevention in AF patients with recurrent thrombo-embolic events despite appropriate anticoagulation.