Preoperative statin therapy for adults undergoing cardiac surgery.

BACKGROUND: Despite significant advances in surgical techniques and perioperative care, people undertaking cardiac surgery due to cardiovascular disease are more prone to the development of postoperative adverse events. Statins (5-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase inhibitors) are well-known for their anti-inflammatory and antioxidant effects and are established for primary and secondary prevention of coronary artery disease. In addition, statins are thought to have clinical benefits in perioperative outcomes in people undergoing cardiac surgery. This review is an update of a review that was first published in 2012 and updated in 2015. OBJECTIVES: To evaluate the benefits and harms of preoperative statin therapy in adults undergoing cardiac surgery compared to standard of care or placebo. SEARCH METHODS: We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 9, 2023), Ovid MEDLINE (1980 to 14 September 2023), and Ovid Embase (1980 to 2023 (week 36)). We applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing any statin treatment before cardiac surgery, for any given duration and dose, versus no preoperative statin therapy (standard of care) or placebo. We excluded trials without a registered trial protocol and trials without approval by an institutional ethics committee. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Primary outcomes were short-term mortality and major adverse cardiovascular events. Secondary outcomes were myocardial infarction, atrial fibrillation, stroke, renal failure, length of intensive care unit (ICU) stay, length of hospital stay and adverse effects related to statin therapy. We reported effect measures as risk ratios (RRs) or mean differences (MDs) with corresponding 95% confidence intervals (CIs). We used the RoB 1 tool to assess the risk of bias in included trials, and GRADE to assess the certainty of the evidence. MAIN RESULTS: We identified eight RCTs (five new to this review) including 5592 participants. Pooled analysis showed that statin treatment before surgery may result in little to no difference in the risk of postoperative short-term mortality (RR 1.36, 95% CI 0.72 to 2.59; I2 = 0%; 6 RCTs, 5260 participants; low-certainty evidence; note 2 RCTs reported 0 events in both groups so RR calculated from 4 RCTs with 5143 participants). We are very uncertain about the effect of statins on major adverse cardiovascular events (RR 0.93, 95% CI 0.77 to 1.13; 1 RCT, 2406 participants; very low-certainty evidence). Statins probably result in little to no difference in myocardial infarction (RR 0.88, 95% CI 0.73 to 1.06; I2 = 0%; 5 RCTs, 4645 participants; moderate-certainty evidence), may result in little to no difference in atrial fibrillation (RR 0.87, 95% CI 0.72 to 1.05; I2 = 60%; 8 RCTs, 5592 participants; low-certainty evidence), and may result in little to no difference in stroke (RR 1.47, 95% CI 0.90 to 2.40; I2 = 0%; 4 RCTs, 5143 participants; low-certainty evidence). We are very uncertain about the effect of statins on renal failure (RR 1.04, 95% CI 0.80 to 1.34; I2 = 57%; 4 RCTs, 4728 participants; very low-certainty evidence). Additionally, statins probably result in little to no difference in length of ICU stay (MD 1.40 hours, 95% CI -1.62 to 4.41; I2 = 43%; 3 RCTs, 4528 participants; moderate-certainty evidence) and overall hospital stay (MD -0.31 days, 95% CI -0.64 to 0.03; I2 = 84%; 5 RCTs, 4788 participants; moderate-certainty evidence). No study had any individual risk of bias domain classified as high. However, two studies were at high risk of bias overall given the classification of unclear risk of bias in three domains. AUTHORS' CONCLUSIONS: In this updated Cochrane review, we found no evidence that statin use in the perioperative period of elective cardiac surgery was associated with any clinical benefit or worsening, when compared with placebo or standard of care. Compared with placebo or standard of care, statin use probably results in little to no difference in MIs, length of ICU stay and overall hospital stay; and may make little to no difference to mortality, atrial fibrillation and stroke. We are very uncertain about the effects of statins on major harmful cardiac events and renal failure. The certainty of the evidence validating this finding varied from moderate to very low, depending on the outcome. Future trials should focus on assessing the impact of statin therapy on mortality and major adverse cardiovascular events.

Antiviral Activities of Mastoparan-L-Derived Peptides against Human Alphaherpesvirus 1.

Human alphaherpesvirus 1 (HSV-1) is a significantly widespread viral pathogen causing recurrent infections that are currently incurable despite available treatment protocols. Studies have highlighted the potential of antimicrobial peptides sourced from Vespula lewisii venom, particularly those belonging to the mastoparan family, as effective against HSV-1. This study aimed to demonstrate the antiviral properties of mastoparans, including mastoparan-L [I5, R8], mastoparan-MO, and [I5, R8] mastoparan, against HSV-1. Initially, Vero cell viability was assessed in the presence of these peptides, followed by the determination of antiviral activity, mechanism of action, and dose-response curves through plaque assays. Structural analyses via circular dichroism and nuclear magnetic resonance were conducted, along with evaluating membrane fluidity changes induced by [I5, R8] mastoparan using fluorescence-labeled lipid vesicles. Cytotoxic assays revealed high cell viability (>80%) at concentrations of 200 µg/mL for mastoparan-L and mastoparan-MO and 50 µg/mL for [I5, R8] mastoparan. Mastoparan-MO and [I5, R8] mastoparan exhibited over 80% HSV-1 inhibition, with up to 99% viral replication inhibition, particularly in the early infection stages. Structural analysis indicated an α-helical structure for [I5, R8] mastoparan, suggesting effective viral particle disruption before cell attachment. Mastoparans present promising prospects for HSV-1 infection control, although further investigation into their mechanisms is warranted.

Influence of antimicrobial peptides on the bacterial membrane curvature and vice versa.

Many factors contribute to bacterial membrane stabilization, including steric effects between lipids, membrane spontaneous curvature, and the difference in the number of neighboring molecules. This forum provides an overview of the physicochemical properties associated with membrane curvature and how this parameter can be tuned to design more effective antimicrobial peptides.

Special Issue: Damage Analysis for Composite Materials: Methods, Testing and Evaluation.

After the Stone, the Bronze, and the Iron Ages, material history is now in the Composite Age [...].

Enhancing Neuronal Cell Uptake of Therapeutic Nucleic Acids with Tetrahedral DNA Nanostructures.

The successful translation of therapeutic nucleic acids (NAs) for the treatment of neurological disorders depends on their safe and efficient delivery to neural cells, in particular neurons. DNA nanostructures can be a promising NAs delivery vehicle. Nonetheless, the potential of DNA nanostructures for neuronal cell delivery of therapeutic NAs is unexplored. Here, tetrahedral DNA nanostructures (TDN) as siRNA delivery scaffolds to neuronal cells, exploring the influence of functionalization with two different reported neuronal targeting ligands: C4-3 RNA aptamer and Tet1 peptide are investigated. Nanostructures are characterized in vitro, as well as in silico using molecular dynamic simulations to better understand the overall TDN structural stability. Enhancement of neuronal cell uptake of TDN functionalized with the C4-3 Aptamer (TDN-Apt), not only in neuronal cell lines but also in primary neuronal cell cultures is demonstrated. Additionally, TDN and TDN-Apt nanostructures carrying siRNA are shown to promote silencing in a process aided by chloroquine-induced endosomal disruption. This work presents a thorough workflow for the structural and functional characterization of the proposed TDN as a nano-scaffold for neuronal delivery of therapeutic NAs and for targeting ligands evaluation, contributing to the future development of new neuronal drug delivery systems based on DNA nanostructures.

State-of-the-Art Macromolecules in Portugal.

This Special Issue presents five contributions covering various topics, as it would be expected for an area as comprehensive and multidisciplinary as Macromolecules [...].

Occurrence and evolutionary conservation analysis of α-helical cationic amphiphilic segments in the human proteome.

The existence of encrypted fragments with antimicrobial activity in human proteins has been thoroughly demonstrated in the literature. Recently, algorithms for the large-scale identification of these segments in whole proteomes were developed, and the pervasiveness of this phenomenon was stated. These algorithms typically mine encrypted cationic and amphiphilic segments of proteins, which, when synthesized as individual polypeptide sequences, exert antimicrobial activity by membrane disruption. In the present report, the human reference proteome was submitted to the software kamal for the uncovering of protein segments that correspond to putative intragenic antimicrobial peptides (IAPs). The assessment of the identity of these segments, frequency, functional classes of parent proteins, structural relevance, and evolutionary conservation of amino acid residues within their corresponding proteins was conducted in silico. Additionally, the antimicrobial and anticancer activity of six selected synthetic peptides was evaluated. Our results indicate that cationic and amphiphilic segments can be found in 2% of all human proteins, but are more common in transmembrane and peripheral membrane proteins. These segments are surface-exposed basic patches whose amino acid residues present similar conservation scores to other residues with similar solvent accessibility. Moreover, the antimicrobial and anticancer activity of the synthetic putative IAP sequences was irrespective to whether these are associated to membranes in the cellular setting. Our study discusses these findings in light of the current understanding of encrypted peptide sequences, offering some insights into the relevance of these segments to the organism in the context of their harboring proteins or as separate polypeptide sequences.

Erythrocytes' surface properties and stiffness predict survival and functional decline in ALS patients.

Erythrocytes play a fundamental role in oxygen delivery to tissues and binding to inflammatory mediators. Evidences suggest that dysregulated erythrocyte function could contribute to the pathophysiology of several neurodegenerative diseases. We aimed to evaluate changes in morphological, biomechanical, and biophysical properties of erythrocytes from amyotrophic lateral sclerosis (ALS) patients, as new areas of study in this disease. Blood samples were collected from ALS patients, comparing with healthy volunteers. Erythrocytes were assessed using atomic force microscopy (AFM) and zeta potential analysis. The patients' motor and respiratory functions were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R) and percentage of forced vital capacity (%FVC). Patient survival was also assessed. Erythrocyte surface roughness was significantly smoother in ALS patients, and this parameter was a predictor of faster decline in ALSFRS-R scores. ALS patients exhibited higher erythrocyte stiffness, as indicated by reduced AFM tip penetration depth, which predicted a faster ALSFRS-R score and respiratory subscore decay. A lower negative charge on the erythrocyte membrane was predictor of a faster ALSFRS-R and FVC decline. Additionally, a larger erythrocyte surface area was an independent predictor of lower survival. These changes in morphological and biophysical membrane properties of ALS patients' erythrocytes, lead to increased cell stiffness and morphological variations. We speculate that these changes might precipitate motoneurons dysfunction and accelerate disease progression. Further studies should explore the molecular alterations related to these observations. Our findings may contribute to dissect the complex interplay between respiratory function, tissue hypoxia, progression rate, and survival in ALS.

Serotonin Syndrome: An Emerging Reality in the Emergency Department.

Serotonin syndrome (SS) is an entity caused by interference with the serotonin metabolism and/or by medications that act as serotonin receptor agonists. The signs and symptoms are nonspecific, making the diagnosis challenging. Treatment depends on the severity of the manifestations. In mild to moderate cases, it typically resolves within the first 24 hours after initiating therapy and discontinuation of the serotoninergic medications. A 42-year-old woman with a previous history of depression was admitted to the hospital due to the voluntary ingestion of multiple tablets of escitalopram 10 mg and venlafaxine 75 mg. Physical examination showed a hyperthermic and diaphoretic patient. Tremor, agitation, bilateral ocular clonus, and spontaneous inferior limb clonus were also present. Hunter's criteria were applied, and the diagnosis of SS was assumed. Supportive and symptomatic treatments were initiated. The evolution was benign, with symptomatic remission in the first 24 hours. In the last decades, a large increase in the use of antidepressants was noted, and, as such, defining SS as rare is no longer appropriate. Delaying the treatment can dictate an increase in morbidity and mortality. It is important to highlight that the diagnosis is mainly clinical as diagnostic criteria may miss out on some cases. As such, clinical awareness of SS's multiplicity of presentations is of utmost importance.

Activity modulation of the Escherichia coli F1FO ATP synthase by a designed antimicrobial peptide via cardiolipin sequestering.

Most antimicrobial peptides (AMPs) exert their microbicidal activity through membrane permeabilization. The designed AMP EcDBS1R4 has a cryptic mechanism of action involving the membrane hyperpolarization of Escherichia coli, suggesting that EcDBS1R4 may hinder processes involved in membrane potential dissipation. We show that EcDBS1R4 can sequester cardiolipin, a phospholipid that interacts with several respiratory complexes of E. coli. Among these, F1FO ATP synthase uses membrane potential to fuel ATP synthesis. We found that EcDBS1R4 can modulate the activity of ATP synthase upon partition to membranes containing cardiolipin. Molecular dynamics simulations suggest that EcDBS1R4 alters the membrane environment of the transmembrane FO motor, impairing cardiolipin interactions with the cytoplasmic face of the peripheral stalk that binds the catalytic F1 domain to the FO domain. The proposed mechanism of action, targeting membrane protein function through lipid reorganization may open new venues of research on the mode of action and design of other AMPs.

Rational Engineering of (S)-Norcoclaurine Synthase for Efficient Benzylisoquinoline Alkaloids Biosynthesis.

(S)-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with (S)-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and the semi-synthetic opioids oxycodone, hydrocodone, and hydromorphone. Unfortunately, the only source of complex BIAs is the opium poppy, leaving the drug supply dependent on poppy crops. Therefore, the bioproduction of (S)-norcoclaurine in heterologous hosts, such as bacteria or yeast, is an intense area of research nowadays. The efficiency of (S)-norcoclaurine biosynthesis is strongly dependent on the catalytic efficiency of NCS. Therefore, we identified vital NCS rate-enhancing mutations through the rational transition-state macrodipole stabilization method at the Quantum Mechanics/Molecular Mechanics (QM/MM) level. The results are a step forward for obtaining NCS variants able to biosynthesize (S)-norcoclaurine on a large scale.

Dengue Virus Capsid Protein Facilitates Genome Compaction and Packaging.

Dengue virus (DENV) is a single-stranded (+)-sense RNA virus that infects humans and mosquitoes, posing a significant health risk in tropical and subtropical regions. Mature virions are composed of an icosahedral shell of envelope (E) and membrane (M) proteins circumscribing a lipid bilayer, which in turn contains a complex of the approximately 11 kb genomic RNA with capsid (C) proteins. Whereas the structure of the envelope is clearly defined, the structure of the packaged genome in complex with C proteins remains elusive. Here, we investigated the interactions of C proteins with viral RNA, in solution and inside mature virions, via footprinting and cross-linking experiments. We demonstrated that C protein interaction with DENV genomes saturates at an RNA:C protein ratio below 1:250. Moreover, we also showed that the length of the RNA genome interaction sites varies, in a multimodal distribution, consistent with the C protein binding to each RNA site mostly in singlets or pairs (and, in some instances, higher numbers). We showed that interaction sites are preferentially sites with low base pairing, as previously measured by 2'-acetylation analyzed by primer extension (SHAPE) reactivity indicating structuredness. We found a clear association pattern emerged: RNA-C protein binding sites are strongly associated with long-range RNA-RNA interaction sites, particularly inside virions. This, in turn, explains the need for C protein in viral genome packaging: the protein has a chief role in coordinating these key interactions, promoting proper packaging of viral RNA. Such sites are, thus, highly consequential for viral assembly, and, as such, may be targeted in future drug development strategies against these and related viruses.

Membrane-Peptide Interactions: From Basics to Current Applications 2.0.

The interaction between peptides and biological membranes is of fundamental importance in the mechanism of numerous membrane-mediated cellular processes, including antimicrobial peptide action, hormone-receptor interactions, drug bioavailability across the blood-brain barrier, and viral fusion processes [...].

Damage Propagation by Cyclic Loading in Drilled Carbon/Epoxy Plates.

Fiber reinforced composites are widely used in the production of parts for load bearing structures. It is generally recognized that composites can be affected both by monotonic and cyclic loading. For assembly purposes, drilling is needed, but holes can act as stress concentration notches, leading to damage propagation and failure. In this work, a batch of carbon/epoxy plates is drilled by different drill geometries, while thrust force is monitored and the hole's surrounding region is inspected. Based on radiographic images, the area and other features of the damaged region are computed for damage assessment. Finally, the specimens are subjected to Bearing Fatigue tests. Cyclic loading causes ovality of the holes and the loss of nearly 10% of the bearing net strength. These results can help to establish an association between the damaged region and the material's fatigue resistance, as larger damage extension and deformation by cyclic stress contribute to the loss of load carrying capacity of parts.

Edible alginate-based films with anti-SARS-CoV-2 activity.

The viability of SARS-CoV-2 on food surfaces and its propagation through the food chain has been discussed by several stakeholders, as it may represent a serious public health problem, bringing new challenges to the food system. This work shows for the first time that edible films can be used against SARS-CoV-2. Sodium alginate-based films containing gallic acid, geraniol, and green tea extract were evaluated in terms of their antiviral activity against SARS-CoV-2. The results showed that all these films have strong in vitro antiviral activity against this virus. However, a higher concentration of the active compound (1.25%) is needed for the film containing gallic acid to achieve similar results to those obtained for lower concentrations of geraniol and green tea extract (0.313%). Furthermore, critical concentrations of the active compounds in the films were used to evaluate their stability during storage. Results showed that gallic acid-loaded films lose their activity from the second week of storage, while films with geraniol and green tea extract only show a drop in activity after four weeks. These results highlight the possibility of using edible films and coatings as antiviral materials on food surfaces or food contact materials, which may help to reduce the spreading of viruses through the food chain.

A mathematical model of fibrinogen-mediated erythrocyte-erythrocyte adhesion.

Erythrocytes are deformable cells that undergo progressive biophysical and biochemical changes affecting the normal blood flow. Fibrinogen, one of the most abundant plasma proteins, is a primary determinant for changes in haemorheological properties, and a major independent risk factor for cardiovascular diseases. In this study, the adhesion between human erythrocytes is measured by atomic force microscopy (AFM) and its effect observed by micropipette aspiration technique, in the absence and presence of fibrinogen. These experimental data are then used in the development of a mathematical model to examine the biomedical relevant interaction between two erythrocytes. Our designed mathematical model is able to explore the erythrocyte-erythrocyte adhesion forces and changes in erythrocyte morphology. AFM erythrocyte-erythrocyte adhesion data show that the work and detachment force necessary to overcome the adhesion between two erythrocytes increase in the presence of fibrinogen. The changes in erythrocyte morphology, the strong cell-cell adhesion and the slow separation of the two cells are successfully followed in the mathematical simulation. Erythrocyte-erythrocyte adhesion forces and energies are quantified and matched with experimental data. The changes observed on erythrocyte-erythrocyte interactions may give important insights about the pathophysiological relevance of fibrinogen and erythrocyte aggregation in hindering microcirculatory blood flow.

2,3-Diphosphoglycerate and the Protective Effect of Pyruvate Kinase Deficiency against Malaria Infection-Exploring the Role of the Red Blood Cell Membrane.

Malaria remains a major world public health problem, contributing to poverty and inequality. It is urgent to find new efficacious tools with few adverse effects. Malaria has selected red blood cell (RBC) alterations linked to resistance against infection, and understanding the protective mechanisms involved may be useful for developing host-directed tools to control Plasmodium infection. Pyruvate kinase deficiency has been associated with resistance to malaria. Pyruvate kinase-deficient RBCs display an increased concentration of 2,3-diphosphoglycerate (2,3-DPG). We recently showed that 2,3-DPG impacts in vitro intraerythrocytic parasite growth, induces a shift of the metabolic profile of infected cells (iRBCs), making it closer to that of noninfected ones (niRBCs), and decreases the number of parasite progenies that invade new RBCs. As an increase of 2,3-DPG content may also have an adverse effect on RBC membrane and, consequently, on the parasite invasion, in this study, we explored modifications of the RBC morphology, biomechanical properties, and RBC membrane on Plasmodium falciparum in vitro cultures treated with 2,3-DPG, using atomic force microscopy (AFM)-based force spectroscopy and other experimental approaches. The presence of infection by P. falciparum significantly increased the rigidity of parasitized cells and influenced the morphology of RBCs, as parasitized cells showed a decrease of the area-to-volume ratio. The extracellular addition of 2,3-DPG also slightly affected the stiffness of niRBCs, making it more similar to that of infected cells. It also changed the niRBC height, making the cells appear more elongated. Moreover, 2,3-DPG treatment influenced the cell surface charge, becoming more negative in treated RBCs than in untreated ones. The results indicate that treatment with 2,3-DPG has only a mild effect on RBCs in comparison with the effect of the presence of the parasite on the host cell. 2,3-DPG is an endogenous host metabolite, which may, in the future, originate a new antimalarial tool with few adverse effects on noninfected cells.

Granulated biomass fly ash coupled with fenton process for pulp and paper wastewater treatment.

The work describes the combination of granulated biomass fly ash (GBFA) with Fenton process to enhance the removal of adsorbable organic halides (AOX) from pulp bleaching wastewater. At optimal operating conditions, wastewater's chemical and biochemical oxygen demand (COD and BOD5, respectively) and colour were also quantified, and operating cost of treatment assessed. For the first time, raw pulp bleaching wastewater was used to granulate BFA, instead of water, reducing the water footprint of the treatment. Five wastewater treatment setups were studied: (i) conventional Fenton process; (ii) GBFA application; (iii) simultaneous application of GBFA and Fenton process; (iv) sequential treatment by GBFA followed by Fenton process; (v) sequential treatment by Fenton process followed by GBFA. The latter yielded the highest AOX removal (60-70%), whilst COD was also reduced (≈15%) and wastewater biodegradability (BOD5/COD) was enhanced from 0.075 to a maximum of 0.134. Another positive feature of the proposed solution was that GBFA were successfully recovered and reused without regeneration, yielding similar AOX removal compared with fresh GBFA. The operating cost of removing 1 g of AOX from the pulp bleaching wastewater by the optimal treatment setup (60-70% removal of AOX) was 14-26% lower than the operating cost of conducting Fenton process alone (50% removal of AOX).

Dengue, West Nile, and Zika Viruses: Potential Novel Antiviral Biologics Drugs Currently at Discovery and Preclinical Development Stages.

Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital malformations (e.g., microcephaly) and, in some situations, death. Moreover, outbreaks also have major socioeconomic repercussions, especially in already vulnerable societies. Thus far, only generic symptoms relief is possible, as there are no specific treatments available yet. Dengvaxia was the world's first dengue vaccine. However, it is not fully effective. Prophylactic approaches against West Nile and Zika viruses are even more limited. Therefore, therapeutic strategies are required and will be discussed hereafter. We will first briefly present these viruses' epidemiology, life cycle and structure. Then, we introduce the clinical presentation, diagnosis approaches and available vaccines. Finally, we list and discuss promising compounds at discovery and preclinical development stages already deposited at the GlobalData database and divided into three main types, according to therapeutic molecule: antibody-based, peptide-based molecules and, other compounds. To conclude, we discuss and compare promising developments, useful for future therapies against these three flaviviruses of major concern to human health.