A Prospective, Multicenter, Real-World Registry of Coronary Lithotripsy in Calcified Coronary Arteries: The REPLICA-EPIC18 Study.

BACKGROUND: Intravascular lithotripsy (IVL) has demonstrated effectiveness in the treatment of calcified lesions in selected patients with stable coronary disease. OBJECTIVES: The authors sought to assess the performance of coronary IVL in calcified coronary lesions in a real-life, all comers, setting. METHODS: The REPLICA-EPIC18 study prospectively enrolled consecutive patients treated with IVL in 26 centers in Spain. An independent core laboratory performed the angiographic analysis and event adjudication. The primary effectiveness endpoint assessed procedural success (successful IVL delivery, final diameter stenosis <20%, and absence of in-hospital major adverse cardiovascular events [MACE]). The primary safety endpoint measured freedom from MACE at 30 days. A predefined substudy compared outcomes between acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. RESULTS: A total of 426 patients (456 lesions) were included, 63% of the patients presenting with ACS. IVL delivery was successful in 99% of cases. Before IVL, 49% of lesions were considered undilatable. The primary effectiveness endpoint was achieved in 66% of patients, with similar rates among CCS patients (68%) and ACS patients (65%). Likewise, there were no significant differences in angiographic success after IVL between CCS and ACS patients. The rate of MACE at 30 days (primary safety endpoint) was 3% (1% in CCS and 5% in ACS patients [P = 0.073]). CONCLUSIONS: Coronary IVL proved to be a feasible and safe procedure in a "real-life" setting, effectively facilitating stent implantation in severely calcified lesions. Patients with ACS on admission showed similar angiographic success rates but showed a trend toward higher 30-day MACE compared with patients with CCS. (REPLICA-EPIC18 study [Registry of Coronary Lithotripsy in Spain]; NCT04298307).

Association between severity of symptoms and minimum mental health treatment duration in humanitarian contexts: a retrospective observational study.

Background: Understanding and optimising mental health and psychosocial support (MHPSS) interventions in humanitarian crises is crucial, particularly for the most prevalent mental health conditions in conflict settings: anxiety, depression, and post-traumatic stress disorder. However, research on what is the most appropriate length of psychological intervention is lacking in this setting. We aimed to establish which factors are most closely related to improvement and to determine the required number of consultations needed to achieve this improvement. Methods: We retrospectively analysed records from 9028 patients allocated to treatment for anxiety, depression, and post-traumatic symptoms from the MHPSS programme in Borno State, Nigeria, from January 2018 to December 2019. Patient characteristics, severity (Clinical Global Impression of Severity Scale, CGI-S scale), and clinical improvement were assessed by an attending counsellor (CGI-I scale) and by the patient (Mental Health Global State, MHGS scale). Improvement was defined as scores 1, 2, and 3 in the Clinical Global Impression of Improvement (CGI-I) scale, and as a decrease of at least 4 points in the MHGS scale. We investigated the associations between the category of symptoms, the severity of illness, and improvement of symptoms using multivariable logistic regression. We used Kaplan-Meier (KM) curves to assess the number of consultations (i.e., time of treatment) needed to achieve improvement of symptoms, by symptom category and symptom severity. Findings: The patients included were referred to treatment for anxiety (n = 3462), depression (n = 3970), or post-traumatic symptoms (n = 1596). Median age was 31 years (range 16-103), and 84.3% were female. Patients categorised as severe were less likely to present improvement according to the CGI-I scale (OR 0.11, 95% CI 0.05-0.25), while none of the other categories of symptoms showed significant results. Overall, three or more consultations were associated with improvement in both scales (OR 3.55, 95% CI 1.47-8.57 for CGI-I; and OR 3.04, 95% CI 2.36-3.90 for MHGS). KM curves for the category of symptoms showed that around 90% of patients with anxiety, depression, or post-traumatic symptoms, as well as those with mild or moderate severity, presented improvement after three consultations, compared with six consultations for those with severe symptoms. Interpretation: Classification by severity among patients with anxiety, depression, or post-traumatic symptoms could predict the probability of improvement, whereas classification by symptoms could not. Our study highlights the importance of classifying patient severity in MHPSS programmes to plan and implement the appropriate duration of care. A major limitation was the number of patients lost to follow up after the first consultation and excluded from the logistic regression and KM analysis. Funding: The study was funded and staffed entirely by Médicos Sin Fronteras (Médecins Sans Frontières), Spain.

Bioactive Components and Biological Activities of Crocus sativus L. Byproducts: A Comprehensive Review.

The production of saffron spice results in numerous byproducts, as only 15 g of spice can be produced from 1 kg of flowers, indicating that over 90% of the saffron flower material is eventually discarded as waste. In view of this, the paper reviews current knowledge on the natural active components in saffron byproducts and their biological activities, aiming to lay a theoretical and scientific foundation for the further utilization. Saffron byproducts contain a variety of phytochemical components, such as flavonoids, anthocyanins, carotenoids, phenolic acids, monoterpenoids, alkaloids, glycosides, and saponins. The activities of saffron byproducts and their mechanisms are also discussed in detail here.

Seasonal malaria chemoprevention in a context of high presumed sulfadoxine-pyrimethamine resistance: malaria morbidity and molecular drug resistance profiles in South Sudan.

BACKGROUND: Seasonal malaria chemoprevention (SMC) using sulfadoxine-pyrimethamine plus amodiaquine (SP-AQ), is a community-based malaria preventive strategy commonly used in the Sahel region of sub-Saharan Africa. However, to date it has not been implemented in East Africa due to high SP resistance levels. This paper is a report on the implementation of SMC outside of the Sahel in an environment with a high level of presumed SP-resistance: five cycles of SMC using SPAQ were administered to children 3-59 months during a period of high malaria transmission (July-December 2019) in 21 villages in South Sudan. METHODS: A population-based SMC coverage survey was combined with a longitudinal time series analysis of health facility and community health data measured after each SMC cycle. SMC campaign effectiveness was assessed by Poisson model. SPAQ molecular resistance markers were additionally analysed from dried blood spots from malaria confirmed patients. RESULTS: Incidence of uncomplicated malaria was reduced from 6.6 per 100 to an average of 3.2 per 100 after SMC administration (mean reduction: 53%) and incidence of severe malaria showed a reduction from 21 per 10,000 before SMC campaign to a mean of 3.3 per 10,000 after each cycle (mean reduction: 84%) in the target group when compared to before the SMC campaign. The most prevalent molecular haplotype associated with SP resistance was the IRNGE haplotype (quintuple mutant, with 51I/59R/108N mutation in pfdhfr + 437G/540E in pfdhps). In contrast, there was a low frequency of AQ resistance markers and haplotypes resistant to both drugs combined (< 2%). CONCLUSIONS: The SMC campaign was effective and could be used as an additional preventive tool in seasonal malaria settings outside of the Sahel, especially in areas where access to health care is unstable. Malaria case load reduction was observed despite the high level of resistance to SP.

Spice and Herb Frauds: Types, Incidence, and Detection: The State of the Art.

There is a necessity to protect the quality and authenticity of herbs and spices because of the increase in the fraud and adulteration incidence during the last 30 years. There are several aspects that make herbs and spices quite vulnerable to fraud and adulteration, including their positive and desirable sensorial and health-related properties, the form in which they are sold, which is mostly powdered, and their economic relevance around the world, even in developing countries. For these reasons, sensitive, rapid, and reliable techniques are needed to verify the authenticity of these agri-food products and implement effective adulteration prevention measures. This review highlights why spices and herbs are highly valued ingredients, their economic importance, and the official quality schemes to protect their quality and authenticity. In addition to this, the type of frauds that can take place with spices and herbs have been disclosed, and the fraud incidence and an overview of scientific articles related to fraud and adulteration based on the Rapid Alert System Feed and Food (RASFF) and the Web of Science databases, respectively, during the last 30 years, is carried out here. Next, the methods used to detect adulterants in spices and herbs are reviewed, with DNA-based techniques and mainly spectroscopy and image analysis methods being the most recommended. Finally, the available adulteration prevention measurements for spices and herbs are presented, and future perspectives are also discussed.

Screening for K13-Propeller Mutations Associated with Artemisinin Resistance in Plasmodium falciparum in Yambio County (Western Equatoria State, South Sudan).

Artemisinin-combined treatments are the recommended first-line treatment of Plasmodium falciparum malaria, but they are being threatened by emerging artemisinin resistance. Mutations in pfk13 are the principal molecular marker for artemisinin resistance. This study characterizes the presence of mutations in pfk13 in P. falciparum in Western Equatoria State, South Sudan. We analyzed 468 samples from patients with symptomatic malaria and found 15 mutations (8 nonsynonymous and 7 synonymous). Each mutation appeared only once, and none were validated or candidate markers of artemisinin resistance. However, some mutations were in the same or following position of validated and candidate resistance markers, suggesting instability of the gene that could lead to resistance. The R561L nonsynonymous mutation was found in the same position as the R561H validated mutation. Moreover, the A578S mutation, which is widespread in Africa, was also reported in this study. We found a high diversity of other pfk13 mutations in low frequency. Therefore, routine molecular surveillance of resistance markers is highly recommended to promptly detect the emergence of resistance-related mutations and to limit their spread.

A hybrid physics-based and data-driven framework for cellular biological systems: Application to the morphogenesis of organoids.

How cells orchestrate their cellular functions remains a crucial question to unravel how they organize in different patterns. We present a framework based on artificial intelligence to advance the understanding of how cell functions are coordinated spatially and temporally in biological systems. It consists of a hybrid physics-based model that integrates both mechanical interactions and cell functions with a data-driven model that regulates the cellular decision-making process through a deep learning algorithm trained on image data metrics. To illustrate our approach, we used data from 3D cultures of murine pancreatic ductal adenocarcinoma cells (PDAC) grown in Matrigel as tumor organoids. Our approach allowed us to find the underlying principles through which cells activate different cell processes to self-organize in different patterns according to the specific microenvironmental conditions. The framework proposed here expands the tools for simulating biological systems at the cellular level, providing a novel perspective to unravel morphogenetic patterns.

Antifungal Effect of Autochthonous Aromatic Plant Extracts on Two Mycotoxigenic Strains of Aspergillus flavus.

This study identified the compounds obtained from four native Dehesa plants, which were holm oak, elm, blackberry and white rockrose, and evaluated their ability to inhibit the growth and production of aflatoxins B1 and B2 of two strains of mycotoxigenic Aspergillus flavus. For this purpose, phenolic compounds present in the leaves and flowers of the plants were extracted and identified, and subsequently, the effect on the growth of A. flavus, aflatoxin production and the expression of a gene related to its synthesis were studied. Cistus albidus was the plant with the highest concentration of phenolic compounds, followed by Quercus ilex. Phenolic acids and flavonoids were mainly identified, and there was great variability among plant extracts in terms of the type and quantity of compounds. Concentrated and diluted extracts were used for each individual plant. The influence on mold growth was not very significant for any of the extracts. However, those obtained from plants of the genus Quercus ilex, followed by Ulmus sp., were very useful for inhibiting the production of aflatoxin B1 and B2 produced by the two strains of A. flavus. Expression studies of the gene involved in the aflatoxin synthesis pathway did not prove to be effective. The results indicated that using these new natural antifungal compounds from the Dehesa for aflatoxin production inhibition would be desirable, promoting respect for the environment by avoiding the use of chemical fungicides. However, further studies are needed to determine whether the specific phenolic compounds responsible for the antifungal activity of Quercus ilex and Ulmus sp. produce the antifungal activity in pure form, as well as to verify the action mechanism of these compounds.

Tumour growth: An approach to calibrate parameters of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment.

To unravel processes that lead to the growth of solid tumours, it is necessary to link knowledge of cancer biology with the physical properties of the tumour and its interaction with the surrounding microenvironment. Our understanding of the underlying mechanisms is however still imprecise. We therefore developed computational physics-based models, which incorporate the interaction of the tumour with its surroundings based on the theory of porous media. However, the experimental validation of such models represents a challenge to its clinical use as a prognostic tool. This study combines a physics-based model with in vitro experiments based on microfluidic devices used to mimic a three-dimensional tumour microenvironment. By conducting a global sensitivity analysis, we identify the most influential input parameters and infer their posterior distribution based on Bayesian calibration. The resulting probability density is in agreement with the scattering of the experimental data and thus validates the proposed workflow. This study demonstrates the huge challenges associated with determining precise parameters with usually only limited data for such complex processes and models, but also demonstrates in general how to indirectly characterise the mechanical properties of neuroblastoma spheroids that cannot feasibly be measured experimentally.

Lateral Approach and Plate Rod Sliding Humeral Osteotomy in Dogs-A Short Case Series.

Five dogs of different breeds and ages were diagnosed with medial compartment disease of the elbow (MCDE). To resolve the condition, a modified technique using a lateral approach and plate/rod sliding humeral osteotomy (SHO) was considered. All dogs recovered uneventfully after surgery. There were no major complications, and all dogs were significantly improved compared to pre-operative condition. This novel technique of adding a pin, based on the alteration of the original technique, optimized resistance to fixation failure. An additional benefit was that the lateral approach was surgically familiar and easily allowed bone grafting. All five dogs treated with the novel approach had improved scores for pain and lameness. This study showed that SHO was more stable and less technically demanding with the addition of an intramedullary pin. This is the first report of a lateral approach and plate rod sliding humeral osteotomy to treat MCDE in dogs.

Antimicrobial Properties of Essential Oils Obtained from Autochthonous Aromatic Plants.

The aim of this work was to determine the antimicrobial activity of the essential oils of six plants widely distributed in the Dehesa of Extremadura, such as Calendula officinalis, Cistus ladanifer, Cistus salviifolius, Cistus multiflorus, Lavandula stoechas, and Rosmarinus officinalis. The content of total phenolic compounds (TPC) and the antimicrobial activity of the essential oils against pathogenic and spoilage bacteria and yeasts as well as aflatoxin-producing molds were determined. A great variability was observed in the composition of the essential oils obtained from the six aromatic plants. The Cistus ladanifer essential oil had the highest content of total phenols (287.32 ppm), followed by the Cistus salviifolius essential oil; and the Rosmarinus officinalis essential oil showed the lowest amount of these compounds. The essential oils showed inhibitory effects on the tested bacteria and also yeasts, showing a maximum inhibition diameter of 11.50 mm for Salmonella choleraesuis and Kregervanrija fluxuum in the case of Cistus ladanifer and a maximum diameter of 9 mm for Bacillus cereus and 9.50 mm for Priceomyces carsonii in the case of Cistus salviifolius. The results stated that antibacterial and antiyeast activity is influenced by the concentration and the plant material used for essential oil preparation. In molds, aflatoxin production was inhibited by all the essential oils, especially the essential oils of Cistus ladanifer and Cistus salviifolius. Therefore, it can be concluded that the essential oils of native plants have significant antimicrobial properties against pathogenic and spoilage microorganisms, so they could be studied for their use in the industry as they are cheap, available, and non-toxic plants that favor the sustainability of the environment of the Dehesa of Extremeña.

DNA Methylation Description of Hippocampus, Cortex, Amygdala, and Blood of Drug-Resistant Temporal Lobe Epilepsy.

Epigenetic changes such as DNA methylation were observed in drug-resistant temporal lobe epilepsy (DR-TLE), a disease that affects 25-30% of epilepsy patients. The main objective is to simultaneously describe DNA methylation patterns associated with DR-TLE in hippocampus, amygdala, surrounding cortex to the epileptogenic zone (SCEZ), and peripheral blood. An Illumina Infinium MethylationEPIC BeadChip array was performed in 19 DR-TLE patients and 10 postmortem non-epileptic controls. Overall, 32, 59, and 3210 differentially methylated probes (DMPs) were associated with DR-TLE in the hippocampus, amygdala, and SCEZ, respectively. These DMP-affected genes were involved in neurotrophic and calcium signaling in the hippocampus and voltage-gated channels in SCEZ, among others. One of the hippocampus DMPs (cg26834418 (CHORDC1)) showed a strong blood-brain correlation with BECon and IMAGE-CpG, suggesting that it could be a potential surrogate peripheral biomarker of DR-TLE. Moreover, in three of the top SCEZ's DMPs (SHANK3, SBF1, and MCF2L), methylation status was verified with methylation-specific qPCR. The differentially methylated CpGs were classified in DMRs: 2 in the hippocampus, 12 in the amygdala, and 531 in the SCEZ. We identified genes that had not been associated to DR-TLE so far such as TBX5, EXOC7, and WRHN. The area with more DMPs associated with DR-TLE was the SCEZ, some of them related to voltage-gated channels. The DMPs found in the amygdala were involved in inflammatory processes. We also found a potential surrogate peripheral biomarker of DR-TLE. Thus, these results provide new insights into epigenetic modifications involved in DR-TLE.

Safety and feasibility of transradial access for percutaneous coronary intervention in chronic total occlusions.

INTRODUCTION AND OBJECTIVES: Transfemoral access is the most frequently used vascular approach in chronic total occlusion percutaneous coronary interventions (CTO-PCI). The aim of this study was to evaluate the safety and feasibility of a transradial access CTO-PCI program and its impact on angiographic and clinical results and length of hospital stay. METHODS: Retrospective multicenter cohort study including 2550 consecutive CTO-PCI procedures included in a multicenter registry with accurate information on vascular access. A total of 896 procedures were performed as radial-only access while 1654 were performed through at least 1 femoral puncture. Clinical and angiographic data were collected. RESULTS: The mean age was 66.3± 11.4 years. The mean Japan-chronic total occlusion score (2.7±0.3) was similar in the 2 groups. Successful revascularization was achieved in 2009 (79.6%) cases, 78.2% and 82.1% in the femoral and radial access cohorts, respectively (P=.002). Periprocedural in-hospital complications were observed in 5.1% and 2.3% (P=.02), with fewer access site-dependant vascular complications in the transradial cohort (2.3% vs 0.2%; P=.009). The mean length of hospital stay was significantly shorter in the transradial access group (0.89±1.4 vs 2.2±3.2 days, P<.001). CONCLUSIONS: A transradial program for CTO-PCI is safe and effective in most CTO lesions. The transradial strategy has fewer vascular complications and shorter length of hospital stay without compromising the success rate.

Neuronal and astrocytic tetraploidy is increased in drug-resistant epilepsy.

AIMS: Epilepsy is one of the most prevalent neurological diseases. A third of patients with epilepsy remain drug-resistant. The exact aetiology of drug-resistant epilepsy (DRE) is still unknown. Neuronal tetraploidy has been associated with neuropathology. The aim of this study was to assess the presence of tetraploid neurons and astrocytes in DRE. METHODS: For that purpose, cortex, hippocampus and amygdala samples were obtained from patients subjected to surgical resection of the epileptogenic zone. Post-mortem brain tissue of subjects without previous records of neurological, neurodegenerative or psychiatric diseases was used as control. RESULTS: The percentage of tetraploid cells was measured by immunostaining of neurons (NeuN) or astrocytes (S100ß) followed by flow cytometry analysis. The results were confirmed by image cytometry (ImageStream X Amnis System Cytometer) and with an alternative astrocyte biomarker (NDRG2). Statistical comparison was performed using univariate tests. A total of 22 patients and 10 controls were included. Tetraploid neurons and astrocytes were found both in healthy individuals and DRE patients in the three brain areas analysed: cortex, hippocampus and amygdala. DRE patients presented a higher number of tetraploid neurons (p = 0.020) and astrocytes (p = 0.002) in the hippocampus than controls. These results were validated by image cytometry. CONCLUSIONS: We demonstrated the presence of both tetraploid neurons and astrocytes in healthy subjects as well as increased levels of both cell populations in DRE patients. Herein, we describe for the first time the presence of tetraploid astrocytes in healthy subjects. Furthermore, these results provide new insights into epilepsy, opening new avenues for future treatment.

Plasmodium falciparum pfhrp2 and pfhrp3 Gene Deletions in Malaria-Hyperendemic Region, South Sudan.

Pfhrp2 and pfhrp3 gene deletions threaten the use of Plasmodium falciparum malaria rapid diagnostic tests globally. In South Sudan, deletion frequencies were 15.6% for pfhrp2, 20.0% for pfhrp3, and 7.5% for double deletions. Deletions were approximately twice as prevalent in monoclonal infections than in polyclonal infections.

Receptor protein tyrosine phosphatase ß/ζ regulates loss of neurogenesis in the mouse hippocampus following adolescent acute ethanol exposure.

Adolescence is a critical period for brain maturation in which this organ is more vulnerable to the damaging effects of ethanol. Administration of ethanol in mice induces a rapid cerebral upregulation of pleiotrophin (PTN), a cytokine that regulates the neuroinflammatory processes induced by different insults and the behavioral effects of ethanol. PTN binds Receptor Protein Tyrosine Phosphatase (RPTP) ß/ζ and inhibits its phosphatase activity, suggesting that RPTPß/ζ may be involved in the regulation of ethanol effects. To test this hypothesis, we have treated adolescent mice with the RPTPß/ζ inhibitor MY10 (60 mg/kg) before an acute ethanol (6 g/kg) administration. Treatment with MY10 completely prevented the ethanol-induced neurogenic loss in the hippocampus of both male and female mice. In flow cytometry studies, ethanol tended to increase the number of NeuN+/activated Caspase-3+ cells particularly in female mice, but no significant effects were found. Ethanol increased Iba1+ cell area and the total marked area in the hippocampus of female mice, suggesting sex differences in ethanol-induced microgliosis. In addition, ethanol reduced the circulating levels of IL-6 and IL-10 in both sexes, although this reduction was only found significant in males and not affected by MY10 treatment. Interestingly, MY10 alone increased the total marked area and the number of Iba1+ cells only in the female hippocampus, but tended to reduce the circulating levels of TNF-α only in male mice. In summary, the data identify a novel modulatory role of RPTPß/ζ on ethanol-induced loss of hippocampal neurogenesis, which seems unrelated to glial and inflammatory responses. The data also suggest sex differences in RPTPß/ζ function that may be relevant to immune responses and ethanol-induced microglial responses.

Effects of Polyphenols and Glucosinolates in Broccoli Extract on Human Gut Microorganisms Based on Simulation In Vitro.

Broccoli extract mainly contains polyphenols and glucosinolates (GSLs). GSLs can be hydrolyzed by gut microorganisms into isothiocyanates (ITCs) and other active substances. These substances have anticancer, anti-inflammatory, antimicrobial, and atherosclerosis-reducing functions. In this study, a high concentration (2000 µmol/L GSLs and 24 µmol/L polyphenols) and a low concentration (83 µmol/L GSLs and 1 µmol/L polyphenols) of broccoli extract were prepared. Gut microorganisms from fresh human feces were cultured to simulate the gut environment in vitro. The GSL content decreased and the types and content of ITCs increased with broccoli extract hydrolysis through cyclic condensation and gas chromatography-mass spectrometry (GC-MS) analyses. Broccoli extract significantly increased probiotics and inhibited harmful bacteria through 16S rDNA sequencing. Based on phylum level analysis, Firmicutes and Lachnospiraceae increased significantly (P < 0.05). At the genus level, both high- and low-concentration groups significantly inhibited Escherichia and increased Bilophila and Alistipes (P < 0.05). The high-concentration group significantly increased Bifidobacterium (P < 0.05). The broccoli extract improved the richness of gut microorganisms and regulated their structure. The GSL hydrolysis was significantly correlated with Bilophila, Lachnospiraceae, Alistipes, Bifidobacterium, Escherichia, and Streptococcus (P < 0.05). These study findings provide a theoretical foundation for further exploring a probiotic mechanism of broccoli extract in the intestine.

A 3D multi-agent-based model for lumen morphogenesis: the role of the biophysical properties of the extracellular matrix.

The correct function of many organs depends on proper lumen morphogenesis, which requires the orchestration of both biological and mechanical aspects. However, how these factors coordinate is not yet fully understood. Here, we focus on the development of a mechanistic model for computationally simulating lumen morphogenesis. In particular, we consider the hydrostatic pressure generated by the cells' fluid secretion as the driving force and the density of the extracellular matrix as regulators of the process. For this purpose, we develop a 3D agent-based-model for lumen morphogenesis that includes cells' fluid secretion and the density of the extracellular matrix. Moreover, this computer-based model considers the variation in the biological behavior of cells in response to the mechanical forces that they sense. Then, we study the formation of the lumen under different-mechanical scenarios and conclude that an increase in the matrix density reduces the lumen volume and hinders lumen morphogenesis. Finally, we show that the model successfully predicts normal lumen morphogenesis when the matrix density is physiological and aberrant multilumen formation when the matrix density is excessive. Supplementary Information: The online version contains supplementary material available at 10.1007/s00366-022-01654-1.