Development Of Use Research Articles

Safety profile of drugs used in non-cystic fibrosis bronchiectasis: a narrative review

Non-cystic fibrosis bronchiectasis is a long-term lung disease characterised by abnormal dilatation of the bronchi, with patients experiencing chronic productive cough and recurrent exacerbations. Currently, there are no licensed drugs for use in bronchiectasis while clinical trials have been conducted to either test new drugs or repurpose existing ones. These drugs target the underlying pathophysiology of bronchiectasis which is known to include infection, inflammation, mucus hypersecretion and retention. Most of the drugs used in daily clinical practice for bronchiectasis are off-label with no randomised trials exploring their safety. This review aims at exploring the safety profile of drugs frequently used in clinical practice to manage bronchiectasis, including antibiotics (e.g. macrolides, aminoglycosides, polymyxins, fluoroquinolones, aztreonam), mucoactive therapy (e.g. hypertonic saline, mannitol, DNase and carbocisteine), anti-inflammatory therapy (inhaled corticosteroids) and drugs currently in development for use in bronchiectasis (e.g. brensocatib, benralizumab and itepekimab).

Diffusion Kinetics in Multi-Phase K-Ion Cathodes

Prussian blue analogues (PBAs) are a framework material that are of great interest for use as cathode materials in Na- and K-ion batteries. Na-ion PBA batteries have been commercialized for use in stationary storage and are now in development for use in electric vehicles. The high operating potential of K-ion PBAs and their compatibility with pre-existing graphite anodes offer the exciting prospect of use in electric vehicles where high specific energy density is necessary [1].The leading cathode material is the Manganese/Iron PBA – K x Mn[Fe(CN)6] y (0<x<2, 0.67<y<1.00). Attempts to maximise the specific capacity of PBA cathodes have been made by eliminating [Fe(CN)6] vacancies (y=1) which incorporates a full x = 2 formula units of K+ ions in the structure through electronic balancing [2]. Whilst making these low-vacancy materials has been made possible by altering the synthesis, optimising the electrochemical performance has proved more challenging [3]. Accessing the full capacity with high retention on cycling is one problem, and achieving the same excellent rate capability of the previously studied high-vacancy PBAs is also non-trivial [3,4] .High-vacancy PBAs have an apparent simple cubic structure, and cycle electrochemically in a solid-solution [4]. Conversely, the low-vacancy PBAs with high K-ion content have coherent structural distortions and undergo phase transitions on cycling [3,5]. The phase transitions are believed to be responsible for poor capacity retention and rate capability [2]. There is also the theory that vacancies provide additional diffusion pathways for K+ ions [Fig. 1] [2]. For the development of this material as a cathode for K-ion batteries to be successful, it is vital that the diffusion kinetics and structural changes on electrochemical cycling are well-understood from a fundamental perspective.For the first time we report diffusion coefficients by using Potentiostatic Intermittent Titration across multiple states of charge of a PBA cathode [6]. Linking the ionic diffusion in the material with the structural phase(s) present from operando X-ray diffraction gives us a mechanistic insight into the cathode’s charge/discharge behaviour. This informs materials design for tuning the structure of the pristine material to optimise its electrochemical performance in a K-ion battery.

Hyperpolarization-Enhanced NMR Spectroscopy of Unaltered Biofluids Using Photo-CIDNP.

The direct and unambiguous detection and identification of individual metabolite molecules present in complex biological mixtures constitute a major challenge in (bio)analytical research. In this context, nuclear magnetic resonance (NMR) spectroscopy has proven to be particularly powerful owing to its ability to provide both qualitative and quantitative atomic-level information on multiple analytes simultaneously in a noninvasive manner. Nevertheless, NMR suffers from a low inherent sensitivity and, moreover, lacks selectivity regarding the number of individual analytes to be studied in a mixture of a myriad of structurally and chemically very different molecules, e.g., metabolites in a biofluid. Here, we describe a method that circumvents these shortcomings via performing selective, photochemically induced dynamic nuclear polarization (photo-CIDNP) enhanced NMR spectroscopy on unmodified complex biological mixtures, i.e., human urine and serum, which yields a single, background-free one-dimensional NMR spectrum. In doing this, we demonstrate that photo-CIDNP experiments on unmodified complex mixtures of biological origin are feasible, can be performed straightforwardly in the native aqueous medium at physiological metabolite concentrations, and act as a spectral filter, facilitating the analysis of NMR spectra of complex biofluids. Due to its noninvasive nature, the method is fully compatible with state-of-the-art metabolomic protocols providing direct spectroscopic information on a small, carefully selected subset of clinically relevant metabolites. We anticipate that this approach, which, in addition, can be combined with existing high-throughput/high-sensitivity NMR methodology, holds great promise for further in-depth studies and development for use in metabolomics and many other areas of analytical research.

Optimizing Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders

Current treatments for diseases in which eosinophils and/or mast cells play an important pathogenic role are often insufficiently effective. One promising target for these disorders is sialic acid immunoglobulin (Ig)-like lectin 8 (Siglec-8), but there are only few monoclonal antibodies (mAbs) against Siglec-8 available, and, so far, Siglec-8-directed therapies have largely focused on unconjugated mAbs, which may lack efficacy. To raise new human mAbs as basis for novel therapeutics, we immunized transgenic (“humanized”) mice with 3T3 cells expressing human full-length Siglec-8 (Siglec-8 FL) or a chimeric mouse/human protein consisting of the V-set domain of mouse CD33 fused with the membrane-proximal C2-set domain of human Siglec-8 or the V-set domain of mouse Siglec-F fused to the membrane-proximal C2-set domain of human Siglec-8. Among 9 unique mAbs we identified and recombinantly produced, 6 (1B6, 1H4, 1B4, 1E1, 1E4, 1E2) recognized Siglec-8 via binding of the V-set domain, 1 (2A3) via binding of the membrane-distal C2-set domain, and 2 (2A7, 2F10) via binding to the membrane-proximal C2-set domain. All mAbs tested were efficiently internalized into Siglec-8+ cells (up to 75% within 4 hours), suggesting their potential to deliver cytotoxic payloads. To assess the value of Siglec-8-directed immunotherapies engaging T or NK cells, we generated tool T cell-engaging Siglec-8/CD3 bispecific antibodies (BiAbs) in the scFv-scFv format as well as Siglec-8 CAR NK cells, using binding sequences from Siglec-8 V-set mAbs. Very low concentrations (10-25 pM) of a Siglec-8/CD3 BiAb built on 1B6 elicited dose-dependent cytolytic activity against EOL-1, HL-60 as well as LUVA cells transduced with Siglec-8 FL. This BiAb also exerted Siglec-8-specific cytotoxicity against HMC 1.2 cells that were enriched for Siglec-8 expression as well as parental LUVA cells, which both display very few Siglec-8 molecules. Similarly, KHYG-1 cells transduced with a Siglec-8 V-set-directed 41BB co-stimulatory domain-containing CAR generated from scFv sequences from 1B6 or 1H4 induced significant cytotoxicity against EOL-1 and RS4;11 cells transduced with Siglec-8 FL. To examine the relationship between the efficacy of T cell and NK cell-engaging therapies and the distance from the target epitope on Siglec-8 to the cell membrane, we engineered human AML and ALL cell line pairs expressing comparable levels of either Siglec-8 FL or an artificial variant of Siglec-8 containing only the V-set domain on the extracellular portion of the protein (Siglec-8 V-set) to bring the V-set domain closer to the cell membrane, and used these cell line pairs as targets for Siglec-8 V-set-directed BiAbs and CAR-modified immune effector cells. Siglec-8 V-set/CD3 BiAbs exerted greater cytotoxicity against AML and ALL cells expressing Siglec-8 V-set than cells expressing Siglec-8 FL. Likewise, Siglec-8 V-set-directed CAR NK cells exerted greater cytotoxicity against AML and ALL cells expressing Siglec-8 V-set than cells expressing Siglec-8 FL, demonstrating that altering the position of the Siglec-8 mAb binding epitope changes the effector functions of Siglec-8 mAb-derived therapies and suggesting membrane-proximal targeting via one of the C2-set domains could enhance Siglec-8-targeted therapies that engage T or NK cells as immune effector cells. To test whether mAbs recognizing one of the C2-set domains could indeed serve as basis for potent therapeutics, we generated a Siglec-8 C2-set/CD3 BiAb in the scFv-scFv format using binding sequences from 2A3 and found it effectively killed EOL-1, ML-1, RS4;11, and LUVA cells transduced with human Siglec-8 FL at very low concentrations. This BiAb also exerted Siglec-8-specific cytotoxicity against Siglec-8-enriched HMC 1.2 cells and parental LUVA cells, which both display Siglec-8 at very low copy number. Likewise, KHYG-1 cells transduced with a Siglec-8 C2-set CAR generated from 2A3 or 2F10 induced significant cytotoxicity against EOL-1 and RS4;11 cells transduced with Siglec-8 FL as well as against Siglec-8-enriched HMC 1.2 cells, albeit to a very modest extent. Together, our data demonstrate Siglec-8-directed immunotherapies can be highly potent, even against target cells expressing very limited copy numbers of Siglec-8 molecules, supporting their further development for use in patients with difficult-to-treat eosinophilic and mast cell disorders.

Antigenic mapping of the hemagglutinin of the H9 subtype influenza A viruses using sera from Japanese quail (Coturnix c. japonica).

Determining the relevant amino acids involved in antigenic drift on the surface protein hemagglutinin (HA) is critical to understand influenza virus evolution and efficient assessment of vaccine strains relative to current circulating strains. We used antigenic cartography to generate an antigenic map of the H9 hemagglutinin (HA) using sera produced in one of the most relevant minor poultry species, Japanese quail. Key antigenic positions were identified and tested to confirm their impact on the antigenic profile. This work provides a better understanding of the antigenic diversity of the H9 HA as it relates to reactivity to quail sera and will facilitate a rational approach for selecting more efficacious vaccines against poultry-origin H9 influenza viruses in minor poultry species.

Cytoplasmic male sterility and abortive seed traits generated through mitochondrial genome editing coupled with allotopic expression of atp1 in tobacco.

Allotopic expression is the term given for the deliberate relocation of gene function from an organellar genome to the nuclear genome. We hypothesized that the allotopic expression of an essential mitochondrial gene using a promoter that expressed efficiently in all cell types except those responsible for male reproduction would yield a cytoplasmic male sterility (CMS) phenotype once the endogenous mitochondrial gene was inactivated via genome editing. To test this, we repurposed the mitochondrially encoded atp1 gene of tobacco to function in the nucleus under the transcriptional control of a CaMV 35S promoter (construct 35S:nATP1), a promoter that has been shown to be minimally expressed in early stages of anther development. The endogenous atp1 gene was eliminated (Δatp1) from 35S:nATP1 tobacco plants using custom-designed meganucleases directed to the mitochondria. Vegetative growth of most 35S:nATP1/Δatp1 plants appeared normal, but upon flowering produced malformed anthers that failed to shed pollen. When 35S:nATP1/Δatp1 plants were cross-pollinated, ovary/capsule development appeared normal, but the vast majority of the resultant seeds were small, largely hollow and failed to germinate, a phenotype akin to the seedless trait known as stenospermocarpy. Characterization of the mitochondrial genomes from three independent Δatp1 events suggested that spontaneous recombination over regions of microhomology and substoichiometric shifting were the mechanisms responsible for atp1 elimination and genome rearrangement in response to exposure to the atp1-targeting meganucleases. Should the results reported here in tobacco prove to be translatable to other crop species, then multiple applications of allotopic expression of an essential mitochondrial gene followed by its elimination through genome editing can be envisaged. Depending on the promoter(s) used to drive the allotopic gene, this technology may have potential application in the areas of: (1) CMS trait development for use in hybrid seed production; (2) seedless fruit production; and (3) transgene containment.

Virulence and Reproduction of Entomopathogenic Nematodes Isolated from a Single Mexican Locality

Abstract Entomopathogenic nematodes (EPNs) are important biological control agents of insect pests. Strains or isolates obtained in specific regions and utilized in situ might contribute to the success of EPNs, since they are adapted to local abiotic conditions. We isolated and identified three isolates each of Heterorhabditis bacteriophora Poinar and Steinernema carpocapsae (Weiser) from soils at Saltillo, Coahuila State, Mexico. These six isolates were bioassayed against larvae of Tenebrio molitor L., using six concentrations of infective juveniles (IJs) per larva (0, 10, 25, 50, 100, 200). EPN-induced mortality of the isolates ranged from 15.2% to 100%. The designated M5 isolate of S. carpocapsae caused 100% mortality after 72 h at concentrations ≥25 IJs/larva with a median lethal concentration of 4.99 IJs/larva. Comparison of mortality levels induced at the same concentration of the six EPN isolates indicated that the Steinernema isolates, in general, induced higher mortality levels than the Heterorhabditis isolates. IJ production in T. molitor larvae also was greatest with the M5 isolate of S. carpocapsae following exposure of larvae to a concentration of 100 IJs/larva with a mean of 17,320 IJs/larva. Based on induced mortality and IJ production, the S. carpocapsae M5 isolate appears to be a viable candidate for further study and possible development for use in insect pest management programs. This study indicates that naturally coexisting local nematode isolates possess different attributes critical for their use as biocontrol agents.

Pesticide biosensors: trends and progresses.

Pesticides, chemical substances extensively employed in agriculture to optimize crop yields, pose potential risks to human and environmental health. Consequently, regulatory frameworks are in place to restrict pesticide residue concentrations in water intended for human consumption. These regulations are implemented to safeguard consumer safety and mitigate any adverse effects on the environment and public health. Although gas chromatography- and liquid chromatography-mass spectrometry (GC-MS and LC-MS) are highly efficient techniques for pesticide quantification, their use is not suitable for real-time monitoring due to the need for sophisticated laboratory pretreatment of samples prior to analysis. Since they would enable analyte detection with selectivity and sensitivity without sample pretreatment, biosensors appear as a promising alternative. These consist of a bioreceptor allowing for specific recognition of the target and of a detection platform, which translates the biological interaction into a measurable signal. As early detection systems remain urgently needed to promptly alert and act in case of pollution, we review here the biosensors described in the literature for pesticide detection to advance their development for use in the field.

Strategy Development for use of Influencers in Communication of Small and Medium-Sized Enterprises (SMEs) with Consumers

In order to retain existing consumers and acquire new ones for the company, one of the basic tasks is to understand their needs and to create a dialogue with them. Effective consumer information and communication with them is important for successful business and for ensuring the company’s competitiveness. Effectiveness means getting maximum effect with less resource consumption. Within the framework of this study, the authors investigate the use of influencers - digital content creators - for communication with consumers for the successful development and competitiveness of small and medium-sized enterprises (SMEs). This research has identified factors that should be taken into account when using influencers in the dialogue with the consumer. The research uses both secondary data analysis and consumer surveys. The study describes the situation regarding the use of influencers in small and medium-sized companies. It was found that influencers are an effective means of communication with consumers. To achieve the goal of the research, three tasks were set: 1) to analyze the theoretical basis of the use of influencers; 2) to describe the use of influencers and their contribution to communication with consumers; 3) to study consumers’ assessment of the activity of influencers. The monographic or descriptive method was used to analyze the theoretical aspects, the analysis of secondary data was used to describe the situation, and a consumer survey was conducted to study the opinion of consumers about the activities of influencers and their contribution to effective communication with consumers.

Structural and Functional Features of Ketoso-3-Epimerases and Their Use in Production of D-Allulose

Rare sugars attract more and more attention as safe, low-calorie sweeteners and functional compounds in the food, pharmaceutical and medical industries. The potential of the rare sugar D-allulose has been proven in a large number of theoretical and applied works but the high cost of its production is a limitation factor for its large-scall production. Epimerization reactions of available sugars leading to the production of D-allulose are catalyzed by enzymes consisting the epimerase group, namely, ketose-3-epimerases. The key goals of ongoing studies on the ketose-3-epimerase family enzymes are focused on the exact mechanisms of their work, improvement of the enzymatic activity and stability in order to achieve high efficiency in the production of D‑allulose. The present review summarizes the latest innovative developments in use of ketose-3-epimerases, as well as optimization of the enzymatic processes of D-allulose production. The structural features of the main enzymes used in the production of this rare sugar, variants of molecular modifications of biocatalysts and prospects for the practical use of the enzyme pathways discussed in this work are considered.

Micropore Evolution and Damage Behavior of Rapid‐Solidified Al–Zn–Mg–Cu Alloy during Hot Plastic Forming

Rapid‐solidified Al–Zn–Mg–Cu alloys possess widespread application prospects owing to their excellent properties, particularly high specific strength. Nevertheless, their further development for use as advanced structural parts is significantly limited by their intrinsic porosity. Herein, the flow stress subroutine and micropore evolution model are combined to predict the cracking and damage behavior of a rapidly solidified Al–Zn–Mg–Cu disk‐shaped part during hot forging. The results reveal that the damage to the part during plastic forming is inversely proportional to the relative density. Reasonable matching between the height‐to‐diameter ratio (H/D) and the initial relative density is the key factor in avoiding cracking and damage to the part. The closure sequence of the micropores is from the center to the outside of the billet. A billet with an H/D of 1 and initial relative density of 0.95 can reach full density after forming, and a damage‐free part can be obtained. These simulation results are verified by analyzing the microstructural characteristics and mechanical properties of the actual forged part.

#4026 ECONOMIC EVALUATION OF ANAEMIA OF CHRONIC KIDNEY DISEASE (CKD): A SYSTEMATIC LITERATURE REVIEW AND MODEL CONCEPTUALISATION

Abstract Background and Aims Anaemia is a common complication of chronic kidney disease (CKD), affecting up to 53.4% of patients with Stage 5 CKD compared to 8.4% of patients with Stage 1 CKD [1]. Anaemia of CKD is associated with increased risk of cardiovascular events and death, increased healthcare resource utilisation (HRU), and reduced health-related quality of life (HRQoL) [2]. Established treatments for anaemia of CKD include erythropoiesis-stimulating agents (ESAs) [1,2]; however, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), targeting both erythropoietin production and iron metabolism (the two key mechanisms of anaemia of CKD), are an emerging class of agents in this indication [3]. The cost and HRQoL burden associated with anaemia of CKD treatment is not well characterised.1 Thus, we conducted a systematic literature review (SLR) to evaluate published economic models (including the cost inputs, time horizon, subgroups, and clinical assumptions used) and HRU data in patients with anaemia of CKD. Findings of the SLR will help guide future economic model development and inform economic evaluation strategies as part of health technology assessment submissions to support daprodustat, an HIF-PHI under development for use in both dialysis-dependent and non-dialysis-dependent patients. Method Relevant publications were identified using structured searching of MEDLINE, Embase, MEDLINE In-Process, Cochrane Controlled Trials Register, and the Cochrane Database of Systematic Reviews from database inception to 10 April 2022 using disease- (e.g. CKD, chronic kidney failure, anaemia) and economic-associated (e.g. economics, economic evaluation, quality-adjusted life-years, model structure) search terms. Additional supplemental searches (conference proceedings [2016–2021], grey literature, and bibliographies) were conducted. Studies were assessed for inclusion or exclusion by two independent reviewers, with any discrepancies resolved by a third reviewer. Objectives were to determine the structure of any published economic models and the availability of health utility data in patients with anaemia and additional complications of CKD, and to examine what cost inputs, time horizons, subgroups, and clinical assumptions are used to inform economic modelling. Results From 1397 citations identified in the searches, 40 primary studies were included in the final analysis. Review of the data revealed an established approach for modelling the ESA cost-effectiveness (i.e. a Markov model with health states defined according to CKD treatment received or anaemia status): most studies were conducted from a North American or European perspective, time horizons varied, and reporting of cycle length was poor. Only one economic evaluation included an HIF-PHI model: given the different mechanisms of action of ESAs and newer treatments, a modelling strategy focused mainly on a Markov approach may not be the most optimal way of assessing cost-effectiveness in anaemia of CKD where HIF-PHIs are used. Considerations of modelling factors that could influence cost-effectiveness of HIF-PHIs are shown in Fig. 1. While existing models typically only stratified patient populations according to age (&amp;lt;65 vs &amp;gt;65 years), for appropriate modelling of treatment effectiveness, the impact of prior treatments (including response to prior ESAs) was also considered. As in every model, comorbidities may also have a role in effect modification and this impact will need to be considered in economic models of anaemia of CKD treatment. Due to the natural history of anaemia in CKD, innovative modelling techniques that retain the Markov approach and which account for respective haemoglobin levels, CKD stage, and potential kidney transplantation should be incorporated into the economic evaluation (Fig. 2). Conclusion Adjustment of existing models using the approaches described may provide more reliable estimates of treatment efficacy in a highly heterogenous population of patients with anaemia of CKD.

I am Robot, Your Health Adviser for Older Adults: Do You Trust My Advice?

AbstractArtificial intelligence and robotic solutions are seeing rapid development for use across multiple occupations and sectors, including health and social care. As robots grow more prominent in our work and home environments, whether people would favour them in receiving useful advice becomes a pressing question. In the context of human–robot interaction (HRI), little is known about people’s advice-taking behaviour and trust in the advice of robots. To this aim, we conducted an experimental study with older adults to measure their trust and compliance with robot-based advice in health-related situations. In our experiment, older adults were instructed by a fictional human dispenser to ask a humanoid robot for advice on certain vitamins and over-the-counter supplements supplied by the dispenser. In the first experimented condition, the robot would give only information-type advice, i.e., neutral informative advice on the supplements given by the human. In the second condition, the robot would give recommendation-type advice, i.e., advice in favour of more supplements than those suggested initially by the human. We measured the trust of the participants in the type of robot-based advice, anticipating that they would be more trusting of information-type advice. Moreover, we measured the compliance with the advice, for participants who received robot-based recommendations, and a closer proxy of the actual use of robot health advisers in home environments or facilities in the foreseeable future. Our findings indicated that older adults continued to trust the robot regardless of the type of advice received, highlighting a type of protective role of robot-based recommendations on their trust. We also found that higher trust in the robot resulted in higher compliance with its advice. The results underpinned the likeliness of older adults welcoming a robot at their homes or health facilities.

Linocin M18 protein from the insect pathogenic bacterium Brevibacillus laterosporus isolates

Brevibacillus laterosporus (Bl) is a Gram-positive and spore-forming bacterium. Insect pathogenic strains have been characterised in New Zealand, and two isolates, Bl 1821L and Bl 1951, are under development for use in biopesticides. However, growth in culture is sometimes disrupted, affecting mass production. Based on previous work, it was hypothesised that Tectiviridae phages might be implicated. While investigating the cause of the disrupted growth, electron micrographs of crude lysates showed structural components of putative phages including capsid and tail-like structures. Sucrose density gradient purification yielded a putative self-killing protein of ~30 kDa. N-terminal sequencing of the ~30 kDa protein identified matches to a predicted 25 kDa hypothetical and a 31.4 kDa putative encapsulating protein homologs, with the genes encoding each protein adjacent in the genomes. BLASTp analysis of the homologs of 31.4 kDa amino acid sequences shared 98.6% amino acid identity to the Linocin M18 bacteriocin family protein of Brevibacterium sp. JNUCC-42. Bioinformatic tools including AMPA and CellPPD defined that the bactericidal potential originated from a putative encapsulating protein. Antagonistic activity of the ~30 kDa encapsulating protein of Bl 1821L and Bl 1951during growth in broth exhibited bacterial autolytic activity. LIVE/DEAD staining of Bl 1821L cells after treatment with the ~30 kDa encapsulating protein of Bl 1821L substantiated the findings by showing 58.8% cells with the compromised cell membranes as compared to 37.5% cells in the control. Furthermore, antibacterial activity of the identified proteins of Bl 1821L was validated through gene expression in a Gram-positive bacterium Bacillus subtilis WB800N.Key Points• Gene encoding the 31.4 kDa antibacterial Linocin M18 protein was identified• It defined the autocidal activity of Linocin M18 (encapsulating) protein• Identified the possible killing mechanism of the encapsulins

Monoclonal antibodies for prophylaxis and therapy of respiratory syncytial virus, SARS-CoV-2, human immunodeficiency virus, rabies and bacterial infections: an update from the World Association of Infectious Diseases and Immunological Disorders and the Italian Society of Antinfective Therapy.

Monoclonal antibodies (mABs) are safe and effective proteins produced in laboratory that may be used to target a single epitope of a highly conserved protein of a virus or a bacterial pathogen. For this purpose, the epitope is selected among those that play the major role as targets for prevention of infection or tissue damage. In this paper, characteristics of the most important mABs that have been licensed and used or are in advanced stages of development for use in prophylaxis and therapy of infectious diseases are discussed. We showed that a great number of mABs effective against virus or bacterial infections have been developed, although only in a small number of cases these are licensed for use in clinical practice and have reached the market. Although some examples of therapeutic efficacy have been shown, not unlike more traditional antiviral or antibacterial treatments, their efficacy is significantly greater in prophylaxis or early post-exposure treatment. Although in many cases the use of vaccines is more effective and cost-effective than that of mABs, for many infectious diseases no vaccines have yet been developed and licensed. Furthermore, in emergency situations, like in epidemics or pandemics, the availability of mABs can be an attractive adjunct to our armament to reduce the impact. Finally, the availability of mABs against bacteria can be an important alternative, when multidrug-resistant strains are involved.

Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action.

Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit-risk ratio is also discussed.

Warp-knitted spacer fabric flexible composites with high stability and low-velocity impact resistance infused by flock-reinforced shear thickening gel

Flexible protective materials with suitable properties are necessary for personal low-velocity impact (LVI) protection. Flock-reinforced shear thickening gel (FRSTG) can absorb energy through its state transition, thereby showing great potential in applications for LVI protection. However, the unstable state of FRSTG with a slight flow behavior challenges its LVI-resistant evaluation and in-depth development in use. Herein, three-dimensional (3D) warp-knitted spacer fabric (WKSF) composites were obtained by infusing FRSTG in high proportions (≥75%). FRSTG was observed to be stably and randomly distributed in the spacer layer of the WKSF, and the desirable flexibility of the composites was confirmed. The LVI protection effect of FRSTG was better than that of shear thickening gel at the same composite ratio, and the composite with an 83% FRSTG proportion absorbed more than 80% of the impact energy. Besides, FRSTG dominated the composites, showing enhanced responsiveness to the impact with increased velocity. Accordingly, this study constructed stable and LVI-resistant 3D flexible composites with FRSTG as the main functional component, which provided new ideas for the development of wearable protective equipment.

Supramolecular β-Cyclodextrin-Quercetin Based Metal-Organic Frameworks as an Efficient Antibiofilm and Antifungal Agent.

The loading of drugs or medicinally active compounds has recently been performed using metal-organic frameworks (MOFs), which are thought to be a new type of porous material in which organic ligands and metal ions can self-assemble to form a network structure. The quercetin (QRC) loading and biofilm application on a cyclodextrin-based metal-organic framework via a solvent diffusion approach is successfully accomplished in the current study. The antibacterial plant flavonoid QRC is loaded onto β-CD-K MOFs to create the composite containing inclusion complexes (ICs) and denoted as QRC:β-CD-K MOFs. The shifting in the chemical shift values of QRC in the MOFs may be the reason for the interaction of QRC with the β-CD-K MOFs. The binding energies and relative contents of MOFs are considerably changed after the formation of QRC:β-CD-K MOFs, suggesting that the interactions took place during the loading of QRC. Confocal laser scanning microscopy (CLSM) showed a reduction in the formation of biofilm. The results of the cell aggregation and hyphal growth are consistent with the antibiofilm activity that is found in the treatment group. Therefore, QRC:β-CD-K MOFs had no effect on the growth of planktonic cells while inhibiting the development of hyphae and biofilm in C. albicans DAY185. This study creates new opportunities for supramolecular β-CD-based MOF development for use in biological research and pharmaceutical production.

Structural Characterization of Several Cement-Based Materials Containing Chemical Additives with Potential Application in Additive Manufacturing.

The rapid increase in additive manufacturing applications in all industries has highlighted the lack of innovative technologies and processes in the construction industry. Several European and international policies are in place to guide the development of the technological processes involved in the construction industry toward a sustainable future. Considering the global concerns regarding this industry, the purpose of this study was to develop new cement-based materials that are capable of accelerated hydration and early strength development for use in additive manufacturing. Ca(NO3)2·4H2O, Al2(SO4)3·18H2O and Na2S2O3·5H2O were used to obtain the accelerating effect in the hydration of Portland cement. Based on results obtained from X-ray diffraction (XRD), scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM/EDX) techniques, as well as low-field nuclear magnetic resonance relaxometry (LF-NMR) techniques, it was demonstrated that all accelerators used have a quickening effect on cement hydration. The addition of Na2S2O3·5H2O or combined Na2S2O3·5H2O and Ca(NO3)2·4H2O led to obtaining new cement-based materials with early strength development and fast hydration of microorganized internal structures, critical characteristics for 3D printing.

MRI assessment of cerebral perfusion in clinical trials.

Neurodegenerative mechanisms affect the brain through a variety of processes that are reflected as changes in brain structure and physiology. Although some biomarkers for these changes are well established, others are at different stages of development for use in clinical trials. One of the most challenging biomarkers to harmonize for clinical trials is cerebral blood flow (CBF). There are several magnetic resonance imaging (MRI) methods for quantifying CBF without the use of contrast agents, in particular arterial spin labeling (ASL) perfusion MRI, which has been increasingly applied in clinical trials. In this review, we present ASL MRI techniques, including strategies for implementation across multiple imaging centers, levels of confidence in assessing disease progression and treatment effects, and details of image analysis.