Usefulness of low-cost simulation models to learning surgical techniques for placenta accreta spectrum: An observational educational study.

OBJECTIVE: To evaluate the utility of low-cost simulation models to teach surgical techniques for placenta accreta spectrum (PAS), included in a multimodal education workshop for PAS. METHODS: This was an observational, survey-based study. Participants were surveyed before and after the use of low-fidelity mannequins to simulate two surgical techniques for PAS (one-step conservative surgery [OSCS] and modified subtotal hysterectomy [MSTH]), within a multimodal educational workshop. The workshops included pre-course preparation, didactics, simulated practice of the techniques using low-cost models, and viewing live surgery. RESULTS: Six OSCS/MSTH training workshops occurred across six countries and a total of 270 participants were surveyed. The responses of 127 certified obstetricians and gynecologists (OB-GYNs) were analyzed. Participants expressed favorable impressions of all components of the simulated session. Perceived anatomical simulator fidelity, scenario realism, educational component effectiveness, and self-assessed performance improvement received ratings of 4-5 (positive end of the Likert scale) from over 90% of respondents. When asked about simulation's role in technique comprehension, comfort level in technique performance, and likelihood of recommending this workshop to others, more than 75% of participants rated these aspects with a score of 4-5 (positively) on the five-point scale. CONCLUSION: Low-cost simulation, within a multimodal education strategy, is a well-accepted intervention for teaching surgical techniques for PAS.

Leveraging patient experience data to guide medicines development, regulation, access decisions and clinical care in the EU.

Patient experience data (PED), provided by patients/their carers without interpretation by clinicians, directly capture what matters more to patients on their medical condition, treatment and impact of healthcare. PED can be collected through different methodologies and these need to be robust and validated for its intended use. Medicine regulators are increasingly encouraging stakeholders to generate, collect and submit PED to support both scientific advice in development programs and regulatory decisions on the approval and use of these medicines. This article reviews the existing definitions and types of PED and demonstrate the potential for use in different settings of medicines' life cycle, focusing on Patient-Reported Outcomes (PRO) and Patient Preferences (PP). Furthermore, it addresses some challenges and opportunities, alluding to important regulatory guidance that has been published, methodological aspects and digitalization, highlighting the lack of guidance as a key hurdle to achieve more systematic inclusion of PED in regulatory submissions. In addition, the article discusses opportunities at European and global level that could be implemented to leverage PED use. New digital tools that allow patients to collect PED in real time could also contribute to these advances, but it is equally important not to overlook the challenges they entail. The numerous and relevant initiatives being developed by various stakeholders in this field, including regulators, show their confidence in PED's value and create an ideal moment to address challenges and consolidate PED use across medicines' life cycle.

New advances in the protective mechanisms of acidic pH after ischemia: Participation of NO.

BACKGROUND: It has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death. OBJECTIVE: To examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model. METHODS: Isolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca2+ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis. RESULTS: AR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR. CONCLUSIONS: Our data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.

Hydrothermal Carbonization of Green Harvesting Residues (GHRs) from Sugar Cane: Effect of Temperature and Water/GHR Ratio on Mass and Energy Yield.

The Valle del Cauca region in Colombia is a significant producer of sugar cane, resulting in large quantities of agricultural residues (green harvesting residues (GHRs)). To ensure sustainable management of these residues, it is crucial to implement proper treatment and disposal technologies while also reusing waste to produce biogas, bioelectricity, or biofuels. The biomass hydrothermal carbonization process offers a means to convert these residues into useful products that serve as fuels or valuable energy materials. This thermal treatment involves the use of water as a solvent and reagent within the biomass's internal structure. In this study, sugar cane cutting residues were collected with relatively high moisture content of 8.5% wt. These residues were subjected to carbonization temperatures ranging from 200 to 300 °C, along with water/GHR ratios between 5/1 and 10/1. The properties of the resulting hydrocarbons were analyzed by using proximate and ultimate analysis. The objective was to produce hydrochar samples with the highest higher heating value (HHV) and energy density compared with the GHRs. The HHV value of the hydrochar showed a significant increase of 69.6% compared with that of the GHRs, reaching 43.5 MJ/kg. Besides, process parameters were optimized for mass yields, energy yields, and ash content. This exploration led us to investigate a new temperature range between 280 and 320 °C, allowing us to establish an optimal value for the hydrochar's properties.

A decade of collaboration in medicines regulation: healthcare professionals engaging with the European Medicines Agency.

The article shows that the input given by healthcare professionals (HCPs) adds value to the regulatory processes surrounding the development, authorisation, and monitoring of a medicine, but is also an instrument for accountability, trust, mutual exchange as well as an insight into the public health issues that matter most to one of the key stakeholder groups the Agency works with. We highlight the role of HCPs in the EU regulatory process and take stock of the first 10 years of the Framework for Interaction with HCPs to describe how practises have evolved over this time to meet the goals of informing, consulting and improving trust in the EU regulatory system. We will analyse what led European Medicines Agency (EMA) to develop this framework through to the next steps and where the interaction might lead in the future.

Draft genome sequences of four Morganella morganii strains isolated from Colombian colorectal cancer patient stool specimens.

We report the draft genome sequences of four Morganella morganii strains isolated from the stools of four patients diagnosed with colorectal cancer (CRC) in Medellín, Colombia. These genomes represent an important addition to the limited number of genomes of M. morganii strains originating from CRC patients currently available.

Benchmarking the Mantel test and derived methods for testing association between distance matrices.

Testing the association between objects is central in ecology, evolution, and quantitative sciences in general. Two types of variables can describe the relationships between objects: point variables (measured on individual objects), and distance variables (measured between pairs of objects). The Mantel test and derived methods have been extensively used for distance variables. Yet, these methods have been criticized due to low statistical power and inflated type I error when spatial autocorrelation is present. Here, we assessed the statistical power between different types of tested variables and the type I error rate over a wider range of autocorrelation intensities than previously assessed, both on univariate and multivariate data. We also illustrated the performance of distance matrix statistics through computational simulations of genetic diversity. We show that the Mantel test and derived methods are not affected by inflated type I error when spatial autocorrelation affects only one variable when investigating correlations, or when either the response or the explanatory variable(s) is affected by spatial autocorrelation while investigating causal relationships. As previously noted, with autocorrelation affecting more variables, inflated type I error could be reduced by modifying the significance threshold. Additionally, the Mantel test has no problem of statistical power when the hypothesis is formulated in terms of distance variables. We highlight that transformation of variable types should be avoided because of the potential information loss and modification of the tested hypothesis. We propose a set of guidelines to help choose the appropriate method according to the type of variables and defined hypothesis.

Thermochemical behavior of agricultural and industrial sugarcane residues for bioenergy applications.

The Colombian sugarcane industry yields significant residues, categorized as agricultural and industrial. While bagasse, a widely studied industrial residue, is employed for energy recovery through combustion, agricultural residues are often left in fields. This study assesses the combustion behavior of these residues in typical collection scenarios. Additionally, it encompasses the characterization of residues from genetically modified sugarcane varieties in Colombia, potentially exhibiting distinct properties not previously documented. Non-isothermal thermogravimetrical analysis was employed to study the thermal behavior of sugarcane industrial residues (bagasse and pith) alongside agricultural residues from two different sugarcane varieties. This facilitated the determination of combustion reactivity through characteristic combustion process temperatures and technical parameters like ignition and combustion indexes. Proximate, elemental, and biochemical analyses revealed slight compositional differences. Agricultural residues demonstrated higher ash content (up to 34%) due to foreign matter adhering during harvesting, as well as soil and mud attachment during collection. Lignin content also varied, being lower for bagasse and pith, attributed to the juice extraction and milling processes that remove soluble lignin. Thermogravimetric analysis unveiled a two-stage burning process in all samples: devolatilization and char formation (~170°C), followed by char combustion (~310°C). Characteristic temperatures displayed subtle differences, with agricultural residues exhibiting lower temperatures and decomposition rates, resulting in reduced ignition and combustion indexes. This indicates heightened combustion reactivity in industrial residues, attributed to their elevated oxygen percentage, leading to more reactive functional groups and greater combustion stability compared to agricultural residues. This information is pertinent for optimizing sugarcane residues utilization in energy applications.

Weather in collection time affects composition of sugarcane agricultural residues.Combustion of sugarcane residues occurs over similar temperature ranges.Industrial residues are more reactive to combustion than agricultural residues.Overall thermal behavior of sugarcane residues depends on their composition.

Stakeholders' Understanding of European Medicine Agency's COVID-19 Vaccine Information Materials in EU and Regional Contexts.

The COVID-19 pandemic posed challenges to communicating accurate information about vaccines because of the spread of misinformation. The European Medicines Agency (EMA) tried to reassure the public by communicating early on about the development and approval of COVID-19 vaccines. The EMA surveyed patients/consumers, healthcare professional organizations, and individual stakeholders, both at the EU level and in an Italian regional context. The objectives of the study were to see if the EMA's core information materials were informative and well-understood and which communication channels were preferred by the public. The main findings showed that individual patients/consumers generally prefer to obtain information about COVID-19 vaccines from the internet or mass media, while organizations and individual healthcare professionals prefer to obtain information from national and international health authorities. Both at EU and local levels, participants had a good understanding of the key messages from regulators and found the materials useful and relevant. However, some improvements were recommended to the visual, text, and dissemination formats, including publishing more information on safety and using a more public-friendly language. Also, it was recommended to maintain the EMA's approach of using media, stakeholder engagement, and web-based formats to communicate about COVID-19 vaccines. In conclusion, user-testing of proactive communication materials aimed to prebunk misinformation during a public health crisis helps to ensure that users understand the development and safety of novel vaccine technologies. This information can then be used as a basis for further evidence-based communication activities by regulators and public health bodies in an emergency context.

Ghrelin Action in the PVH of Male Mice: Accessibility, Neuronal Targets, and CRH Neurons Activation.

The hormone ghrelin displays several well-characterized functions, including some with pharmaceutical interest. The receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), is expressed in the hypothalamic paraventricular nucleus (PVH), a critical hub for the integration of metabolic, neuroendocrine, autonomic, and behavioral functions. Here, we performed a neuroanatomical and functional characterization of the neuronal types mediating ghrelin actions in the PVH of male mice. We found that fluorescent ghrelin mainly labels PVH neurons immunoreactive for nitric oxide synthase 1 (NOS1), which catalyze the production of nitric oxide [NO]). Centrally injected ghrelin increases c-Fos in NOS1 PVH neurons and NOS1 phosphorylation in the PVH. We also found that a high dose of systemically injected ghrelin increases the ghrelin level in the cerebrospinal fluid and in the periventricular PVH, and induces c-Fos in NOS1 PVH neurons. Such a high dose of systemically injected ghrelin activates a subset of NOS1 PVH neurons, which do not express oxytocin, via an arcuate nucleus-independent mechanism. Finally, we found that pharmacological inhibition of NO production fully abrogates ghrelin-induced increase of calcium concentration in corticotropin-releasing hormone neurons of the PVH whereas it partially impairs ghrelin-induced increase of plasma glucocorticoid levels. Thus, plasma ghrelin can directly target a subset of NO-producing neurons of the PVH that is involved in ghrelin-induced activation of the hypothalamic-pituitary-adrenal neuroendocrine axis.

Molecular Characterization of Trypanosoma cruzi Reactivation and Follow-up in a Case Series of People With HIV.

We characterize Trypanosoma cruzi infections from blood and cerebrospinal fluid samples in a case series of people with human immunodeficiency virus and Chagas disease. We identify different infecting T. cruzi populations, highlighting the usefulness of real-time polymerase chain reaction for Chagas disease reactivation diagnosis and evaluation of treatment response.

Artificial intelligence and real-world data for drug and food safety - A regulatory science perspective.

In 2013, the Global Coalition for Regulatory Science Research (GCRSR) was established with members from over ten countries (www.gcrsr.net). One of the main objectives of GCRSR is to facilitate communication among global regulators on the rise of new technologies with regulatory applications through the annual conference Global Summit on Regulatory Science (GSRS). The 11th annual GSRS conference (GSRS21) focused on "Regulatory Sciences for Food/Drug Safety with Real-World Data (RWD) and Artificial Intelligence (AI)." The conference discussed current advancements in both AI and RWD approaches with a specific emphasis on how they impact regulatory sciences and how regulatory agencies across the globe are pursuing the adaptation and oversight of these technologies. There were presentations from Brazil, Canada, India, Italy, Japan, Germany, Switzerland, Singapore, the United Kingdom, and the United States. These presentations highlighted how various agencies are moving forward with these technologies by either improving the agencies' operation and/or preparing regulatory mechanisms to approve the products containing these innovations. To increase the content and discussion, the GSRS21 hosted two debate sessions on the question of "Is Regulatory Science Ready for AI?" and a workshop to showcase the analytical data tools that global regulatory agencies have been using and/or plan to apply to regulatory science. Several key topics were highlighted and discussed during the conference, such as the capabilities of AI and RWD to assist regulatory science policies for drug and food safety, the readiness of AI and data science to provide solutions for regulatory science. Discussions highlighted the need for a constant effort to evaluate emerging technologies for fit-for-purpose regulatory applications. The annual GSRS conferences offer a unique platform to facilitate discussion and collaboration across regulatory agencies, modernizing regulatory approaches, and harmonizing efforts.

Public information on shortages in the EU/EEA: improvements made between 2018 and 2020.

BACKGROUND: In July 2019, the Heads of Medicines Agencies/European Medicines Agency (HMA/EMA) Task Force on Availability of Authorised Medicines for Human and Veterinary Use (TFAAM) published good practice guidance which provides key principles for European Union (EU) regulatory authorities for communication on shortages and availability issues. The use of a shortage catalogue was a key recommendation. OBJECTIVES: To assess how EU/European Economic Area (EEA) national competent authorities have implemented the recommendations of the good practice guidance. METHODS: A survey was run in 2020 among EU/EEA national competent authorities to assess communication practices. The results were compared with those of a similar survey carried out 2 years earlier, before publication of the guidance. The survey covered human medicines only and was sent to 31 authorities: one per EU/EEA member state (and two to Germany's two medicines regulatory authorities). RESULTS: In 2020, 81% of authorities (25/31) had a dedicated public shortage catalogue on their website. This was an increase from 74% (23/31) in 2018, when a similar survey was run. In future this is expected to increase to 87% with two more member states making plans to implement catalogues. Although many member states publish information on shortages there is still selection in terms of the details that are being published, and there is further scope to extend the information currently provided. CONCLUSION: Since publication of the EMA/HMA good practice guide in 2019, transparency has increased across the EU/EEA, and public catalogues of shortages are now a routine tool used by many medicines agencies.Further opportunities to improve transparency on supply issues lie ahead with the EMA network strategy to 2025, the revised EU pharmaceutical legislation and the new legal mandate reinforcing the role of the EMA.

Thyroid hormone disorder and the heart: The role of cardiolipin in calcium handling.

NEW FINDINGS: What is the central question of this study? Do alterations in thyroid status affect haemodynamic parameters and echocardiographic measurements in the rat postnatal heart, and calcium handling, contractility, relaxation and cardiolipin content in isolated rat cardiomyocytes? What is the main finding and its importance? An imbalance in phospholipids of the mitochondrial membrane such as cardiolipin is related to defects in mitochondrial function. T3 -dependent cardiolipin signals contribute to the maintenance of mitochondrial homeostasis and involve Ca2+ handling, this pathway being more important in hypothyroidism. ABSTRACT: The objective of this study was to evaluate whether alterations in thyroid status affect (1) haemodynamic parameters and echocardiographic measurements in the rat postnatal heart, and (2) calcium handling, contractility, relaxation and cardiolipin content in isolated rat cardiomyocytes. Sprague-Dawley rats aged 2 months treated with T3 (hyperthyroid, 20 µg/100 g body weight) or 0.02% methimazole (hypothyroid, w/v) for 28 days. Heart function was evaluated by echocardiography. Measurements of mean arterial pressure (MAP), heart rate, Ca2+ transients, cardiomyocyte shortening, number of spontaneous contractions per minute and cardiolipin (CL) content were performed. Thyroid disorders were associated with changes in pacemaker activity without modifications of MAP. Thyroid disorder induced changes in left ventricular diameter which were correlated with modifications of cardiac contractility (altered cell shortening and sarcoplasmic reticulum Ca2+ content). Endocrine disorders altered cardiomyocyte relaxation (reduction in the time to 50% re-lengthening and the time to 50% Ca2+ decay). Thyroid disorder increased the number of spontaneous contractions per minute (an index of pro-arrhythmogenic behaviour). CL content was increased only in hypothyroid rats. Changes in CL content, CL composition and CL-protein interaction in mitochondria from hypothyroid animals are responsible for alterations of contractile and relaxation cardiac function. This mechanism may be not be involved in T3 -treated rats. Maintenance of euthyroidism is of crucial importance to preserve cardiac performance. An imbalance in relation to phospholipids of the mitochondrial membrane such as CL is related to defects in mitochondrial function. T3 -dependent CL signals contribute to the maintenance of mitochondrial homeostasis and involve Ca2+ handling, this pathway being more important in hypothyroidism.

Dielectric Strength of Nanofluid-Impregnated Transformer Solid Insulation.

The interest in developing new fluids that can be used as dielectric liquids for transformers has driven the research on dielectric nanofluids in the last years. A number of authors have reported promising results on the electrical and thermal properties of dielectric nanofluids. Less attention has been paid to the interaction of these fluids with the cellulose materials that constitute the solid insulation of the transformers. In the present study, the dielectric strength of cellulose insulation is investigated, comparing its behavior when it is impregnated with transformer mineral oil and when it is impregnated with a dielectric nanofluid. The study includes the analysis of the AC breakdown voltage and the impulse breakdown voltage of the samples. Large improvements were observed on the AC breakdown voltages of the specimens impregnated with nanofluids, while the enhancements were lower in the case of the impulse tests. The reasons for the increase in AC breakdown voltage were investigated, considering the dielectric properties of the nanofluids used to impregnate the samples of cellulose. The analysis was completed with a finite element study that revealed the effect of the nanoparticles on the electric field distribution within the test cell, and its role in the observed enhancement.

Whole genome assembly of the armored loricariid catfish Ancistrus triradiatus highlights herbivory signatures.

The catfish Ancistrus triradiatus belongs to the species-rich family Loricariidae. Loricariids display remarkable traits such as herbivory, a benthic lifestyle, the absence of scales but the presence of dermal bony plates. They are exported as ornamental fish worldwide, with escaped fishes becoming a threat locally. Although genetic and phylogenetic studies are continuously increasing and developmental genetic investigations are underway, no genome assembly has been formally proposed for Loricariidae yet. We report a high-quality genome assembly of Ancistrus triradiatus using long and short reads, and a newly assembled transcriptome. The genome assembly is composed of 9530 scaffolds, including 85.6% of ray-finned fish BUSCOs, and 26,885 predicted protein-coding genes. The genomic GC content is higher than in other catfishes, reflecting the higher metabolism associated with herbivory. The examination of the SCPP gene family indicates that the genes presumably triggering scale loss when absent, are present in the scaleless A. triradiatus, questioning their explanatory role. The analysis of the opsin gene repertoire revealed that gene losses associated to the nocturnal lifestyle of catfishes were not entirely found in A. triradiatus, as the UV-sensitive opsin 5 is present. Finally, most gene family expansions were related to immunity except the gamma crystallin gene family which controls pupil shape and sub-aquatic vision. Thus, the genome of A. triradiatus reveals that fish herbivory may be related to the photic zone habitat, conditions metabolism, photoreception and visual functions. This genome is the first for the catfish suborder Loricarioidei and will serve as backbone for future genetic, developmental and conservation studies.

Translocating Peptides of Biomedical Interest Obtained from the Spike (S) Glycoprotein of the SARS-CoV-2.

At the beginning of 2020, the pandemic caused by the SARS-CoV-2 virus led to the fast sequencing of its genome to facilitate molecular engineering strategies to control the pathogen's spread. The spike (S) glycoprotein has been identified as the leading therapeutic agent due to its role in localizing the ACE2 receptor in the host's pulmonary cell membrane, binding, and eventually infecting the cells. Due to the difficulty of delivering bioactive molecules to the intracellular space, we hypothesized that the S protein could serve as a source of membrane translocating peptides. AHB-1, AHB-2, and AHB-3 peptides were identified and analyzed on a membrane model of DPPC (dipalmitoylphosphatidylcholine) using molecular dynamics (MD) simulations. An umbrella sampling approach was used to quantify the energy barrier necessary to cross the boundary (13.2 to 34.9 kcal/mol), and a flat-bottom pulling helped to gain a deeper understanding of the membrane's permeation dynamics. Our studies revealed that the novel peptide AHB-1 exhibited comparable penetration potential of already known potent cell-penetrating peptides (CPPs) such as TP2, Buforin II, and Frenatin 2.3s. Results were confirmed by in vitro analysis of the peptides conjugated to chitosan nanoparticles, demonstrating its ability to reach the cytosol and escape endosomes, while maintaining high biocompatibility levels according to standardized assays.