Music for pain relief of minor procedures in term neonates.

BACKGROUND: Music for neonatal pain has not been exclusively studied in term neonates in a well-designed trial compared to the standard of care. This study aims to assess the effectiveness of music intervention as an adjuvant in relieving acute pain in term newborns undergoing minor painful procedures. METHODS: This randomized, controlled, blinded trial included any term neonate undergoing heel prick. Both control and intervention groups received oral sucrose 2 min before heel prick. Intervention group was exposed to 'Bedtime Mozart' lullaby recorded music via bedside speakers. Pain was measured using Neonatal Infant Pain Scale (NIPS) at 1-min intervals. Investigators were blinded using noise-canceling headphones that played random music. RESULTS: A total of 100 neonates were enrolled. Mean gestational age was 39.2 weeks, and mean duration of the procedure was 113 s. Music group was found to have significantly lower pain scores [OR = 0.42 (0.31, 0.56), p < 0.001]. Baseline NIPS scores were similar across groups and there was no interaction effect between groups and time. When NIPS were categorized as pain and no pain, there continued to be statistically significant lower NIPS scores in the music group (p < 0.001). CONCLUSION: Recorded music, in addition to sucrose, is efficacious in reducing pain, encouraging its use in term neonates. IMPACT: Recorded music effectively reduces pain induced by minor procedures in term neonates. Clinical studies have shown that live and recorded music induces changes in vital signs and pain scores in the NICU's predominantly preterm population. Most of these studies were also conducted in the white ethnic population. Our study objectively proves reduction in pain scores by using recorded music in a randomized, controlled, blinded study of predominantly non-white, term neonates. Recorded music is effective in reducing acute pain in term neonates and can be widely used even in low-resource nurseries.

Patient with adrenal insufficiency due to a de novo mutation in the NR0B1 gene.

Objectives: Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations. Case presentation: We present the case of a 26-day old male newborn with symptoms consistent with adrenal insufficiency, hyponatremia, and hyperkalemia. Following NaCl and fludrocortisone supplementation, the patient remained clinically stable. 17-OH-progesterone testing excluded congenital adrenal hyperplasia. The rest of hormones were within normal limits, except for adrenocorticotropic hormone (ACTH), which was significantly elevated, and aldosterone, which was below the reference value. Further testing included very long chain fatty acids to exclude adrenoleukodystrophy, the CYP11B2 gene (aldosterone synthase), and an MRI to screen for other morphological abnormalities. All tests yielded normal results. Finally, after cortisol deficiency was detected, expanded genetic testing revealed a mutation in the NR0B1 gene, which led to a diagnosis of congenital adrenal hypoplasia. Conclusions: Diagnosis of congenital adrenal hypoplasia is challenging due to the heterogeneity of both clinical manifestations and laboratory abnormalities. As a result, diagnosis requires close monitoring and genetic testing.

Ink Material Selection and Optical Design Considerations in DLP 3D Printing.

Digital light processing (DLP) 3D printing has become a powerful manufacturing tool for the fast fabrication of complex functional structures. The rapid progress in DLP printing has been linked to research on optical design factors and ink selection. This critical review highlights the main challenges in the DLP printing of photopolymerizable inks. The kinetics equations of photopolymerization reaction in a DLP printer are solved, and the dependence of curing depth on the process optical parameters and ink chemical properties are explained. Developments in DLP platform design and ink selection are summarized, and the roles of monomer structure and molecular weight on DLP printing resolution are shown by experimental data. A detailed guideline is presented to help engineers and scientists to select inks and optical parameters for fabricating functional structures for multi-material and 4D printing applications.

The Proof-of-Concept of MBA121, a Tacrine-Ferulic Acid Hybrid, for Alzheimer's Disease Therapy.

Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer's disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine-ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good ß-amyloid (Aß) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as Aß1-40, Aß1-42, and H2O2, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the Aß plaque burden in the cerebral cortex and hippocampus in APPswe/PS1ΔE9 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD.

Additive Manufacturing of Thermoplastic Polyurethane-Cork Composites for Material Extrusion Technologies.

Among the material extrusion technologies of additive manufacturing, fused granular fabrication is playing a bigger role in the industry. The increase in the size of printers demands extrusion systems with higher deposition rates that facilitate printing larger parts in shorter times with a need for cost reduction. This cost reduction in fused granular fabrication systems is due to the utilisation of pellets as the material source for the prints, such as pellets that are the most common way of distributing polymeric materials in industry and do not need the usual previous transformation into filaments. Most of the polymers in the industry can be found in the shape of pellets, so the opportunities for developing new materials beside the traditional filaments found in the market are expanding. In this research, a novel composite material has been developed based on the blending of commercial thermoplastic polyurethane (TPU) and cork particles obtained from industrial waste at different concentrations. These materials have been processed at a laboratory scale, and their mechanical, thermal and rheological properties have been studied. Despite a 53.52% reduction in the maximum stress on the x-axis, an 81.82% decrease in the values obtained with specimens oriented on the z-axis and a shortage in the deformation values, the results reveal a remarkable weight reduction leading to 21.31% when compared to the TPU of the blends,. These results may open a path to further explore these blends and find suitable applications in industry as proposed.

Modulation of Cell Response through the Covalent Binding of Fibronectin to Titanium Substrates.

Titanium (Ti-6Al-4V) substrates were functionalized through the covalent binding of fibronectin, and the effect of the existence of this extracellular matrix protein on the surface of the material was assessed by employing mesenchymal stem cell (MSC) cultures. The functionalization process comprised the usage of the activation vapor silanization (AVS) technique to deposit a thin film with a high surface density of amine groups on the material, followed by the covalent binding of fibronectin to the amine groups using the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) crosslinking chemistry. The biological effect of the fibronectin on murine MSCs was assessed in vitro. It was found that functionalized samples not only showed enhanced initial cell adhesion compared with bare titanium, but also a three-fold increase in the cell area, reaching values comparable to those found on the polystyrene controls. These results provide compelling evidence of the potential to modulate the response of the organism to an implant through the covalent binding of extracellular matrix proteins on the prosthesis.

Resistance to Degradation of Silk Fibroin Hydrogels Exposed to Neuroinflammatory Environments.

Central nervous system (CNS) diseases represent an extreme burden with significant social and economic costs. A common link in most brain pathologies is the appearance of inflammatory components that can jeopardize the stability of the implanted biomaterials and the effectiveness of therapies. Different silk fibroin scaffolds have been used in applications related to CNS disorders. Although some studies have analyzed the degradability of silk fibroin in non-cerebral tissues (almost exclusively upon non-inflammatory conditions), the stability of silk hydrogel scaffolds in the inflammatory nervous system has not been studied in depth. In this study, the stability of silk fibroin hydrogels exposed to different neuroinflammatory contexts has been explored using an in vitro microglial cell culture and two in vivo pathological models of cerebral stroke and Alzheimer's disease. This biomaterial was relatively stable and did not show signs of extensive degradation across time after implantation and during two weeks of in vivo analysis. This finding contrasted with the rapid degradation observed under the same in vivo conditions for other natural materials such as collagen. Our results support the suitability of silk fibroin hydrogels for intracerebral applications and highlight the potentiality of this vehicle for the release of molecules and cells for acute and chronic treatments in cerebral pathologies.

Preclinical examination of early-onset thalamic-cortical seizures after hemispheric stroke.

OBJECTIVE: Ischemic stroke is one of the main causes of death and disability worldwide and currently has limited treatment options. Electroencephalography (EEG) signals are significantly affected in stroke patients during the acute stage. In this study, we preclinically characterized the brain electrical rhythms and seizure activity during the hyperacute and late acute phases in a hemispheric stroke model with no reperfusion. METHODS: EEG signals and seizures were studied in a model of hemispheric infarction induced by permanent occlusion of the middle cerebral artery (pMCAO), which mimics the clinical condition of stroke patients with permanent ischemia. Electrical brain activity was also examined using a photothrombotic (PT) stroke model. In the PT model, we induced a similar (PT group-1) or smaller (PT group-2) cortical lesion than in the pMCAO model. For all models, we used a nonconsanguineous mouse strain that mimics human diversity and genetic variation. RESULTS: The pMCAO hemispheric stroke model exhibited thalamic-origin nonconvulsive seizures during the hyperacute stage that propagated to the thalamus and cortex. The seizures were also accompanied by progressive slowing of the EEG signal during the acute phase, with elevated delta/theta, delta/alpha, and delta/beta ratios. Cortical seizures were also confirmed in the PT stroke model of similar lesions as in the pMCAO model, but not in the PT model of smaller injuries. SIGNIFICANCE: In the clinically relevant pMCAO model, poststroke seizures and EEG abnormalities were inferred from recordings of the contralateral hemisphere (noninfarcted hemisphere), emphasizing the reciprocity of interhemispheric connections and that injuries affecting one hemisphere had consequences for the other. Our results recapitulate many of the EEG signal hallmarks seen in stroke patients, thereby validating this specific mouse model for the examination of the mechanistic aspects of brain function and for the exploration of the reversion or suppression of EEG abnormalities in response to neuroprotective and anti-epileptic therapies.

Application of single cell force spectroscopy (SCFS) to the assessment of cell adhesion to peptide-decorated surfaces.

The adhesion forces of cells to peptide-coated functionalized materials were assessed through the Single Cell Force Spectroscopy (SCFS) technique in order to develop a methodology that allows the fast selection of peptide motifs that favor the interaction between cells and the biomaterial. Borosilicate glasses were functionalized using the activated vapor silanization process (AVS) and subsequently decorated with an RGD- containing peptide using the EDC/NHS crosslinking chemistry. It is shown that the RGD-coated glass induces larger attachment forces on mesenchymal stem cell cultures (MSCs), compared to the bare glass substrates. These higher forces correlate well with the enhanced adhesion of the MSCs observed on RGD-coated substrates through conventional adhesion cell cultures and inverse centrifugation tests. The methodology based on the SCFS technique presented in this work constitutes a fast procedure for the screening of new peptides or their combinations to select candidates that may enhance the response of the organism to the implant of the functionalized biomaterials.

MoS2-Carbon Nanodots as a New Electrochemiluminescence Platform for Breast Cancer Biomarker Detection.

In this work, we present the combination of two different types of nanomaterials, 2D molybdenum disulfide nanosheets (MoS2-NS) and zero-dimensional carbon nanodots (CDs), for the development of a new electrochemiluminescence (ECL) platform for the early detection and quantification of the biomarker human epidermal growth factor receptor 2 (HER2), whose overexpression is associated with breast cancer. MoS2-NS are used as an immobilization platform for the thiolated aptamer, which can recognize the HER2 epitope peptide with high affinity, and CDs act as coreactants of the anodic oxidation of the luminophore [Ru(bpy)3]2+. The HER2 biomarker is detected by changes in the ECL signal of the [Ru(bpy)3]2+/CD system, with a low detection limit of 1.84 fg/mL and a wide linear range. The proposed method has been successfully applied to detect the HER2 biomarker in human serum samples.

The Spider Silk Standardization Initiative (S3I): A powerful tool to harness biological variability and to systematize the characterization of major ampullate silk fibers spun by spiders from suburban Sydney, Australia.

The true stress-true strain curves of 11 Australian spider species from the Entelegynae lineage were tensile tested and classified based on the values of the alignment parameter, α*, in the framework of the Spider Silk Standardization Initiative (S3I). The application of the S3I methodology allowed the determination of the alignment parameter in all cases, and were found to range between α* = 0.03 and α* = 0.65. These data, in combination with previous results on other species included in the Initiative, were exploited to illustrate the potential of this approach by testing two simple hypotheses on the distribution of the alignment parameter throughout the lineage: (1) whether a uniform distribution may be compatible with the values obtained from the studied species, and (2) whether any trend may be established between the distribution of the α* parameter and phylogeny. In this regard, the lowest values of the α* parameter are found in some representatives of the Araneidae group, and larger values seem to be found as the evolutionary distance from this group increases. However, a significant number of outliers to this apparent general trend in terms of the values of the α* parameter are described.

Axonal Guidance Using Biofunctionalized Straining Flow Spinning Regenerated Silk Fibroin Fibers as Scaffold.

After an injury, the limited regenerative capacity of the central nervous system makes the reconnection and functional recovery of the affected nervous tissue almost impossible. To address this problem, biomaterials appear as a promising option for the design of scaffolds that promote and guide this regenerative process. Based on previous seminal works on the ability of regenerated silk fibroin fibers spun through the straining flow spinning (SFS) technique, this study is intended to show that the usage of functionalized SFS fibers allows an enhancement of the guidance ability of the material when compared with the control (nonfunctionalized) fibers. It is shown that the axons of the neurons not only tend to follow the path marked by the fibers, in contrast to the isotropic growth observed on conventional culture plates, but also that this guidance can be further modulated through the biofunctionalization of the material with adhesion peptides. Establishing the guidance ability of these fibers opens the possibility of their use as implants for spinal cord injuries, so that they may represent the core of a therapy that would allow the reconnection of the injured ends of the spinal cord.

Harmonization of indirect reference intervals calculation by the Bhattacharya method.

OBJECTIVES: The aim of this study was to harmonize the criteria for the Bhattacharya indirect method Microsoft Excel Spreadsheet for reference intervals calculation to reduce between-user variability and use these criteria to calculate and evaluate reference intervals for eight analytes in two different years. METHODS: Anonymized laboratory test results from outpatients were extracted from January 1st 2018 to December 31st 2019. To assure data quality, we examined the monthly results from an external quality control program. Reference intervals were determined by the Bhattacharya method with the St Vincent's hospital Spreadsheet firstly using original criteria and then using additional harmonized criteria defined in this study. Consensus reference intervals using the additional harmonized criteria were calculated as the mean of four users' lower and upper reference interval results. To further test the operation criteria and robustness of the obtained reference intervals, an external user validated the Spreadsheet procedure. RESULTS: The extracted test results for all selected laboratory tests fulfilled the quality criteria and were included in the present study. Differences between users in calculated reference intervals were frequent when using the Spreadsheet. Therefore, additional criteria for the Spreadsheet were proposed and applied by independent users, such as: to set central bin as the mean of all the data, bin size as small as possible, at least three consecutive bins and a high proportion of bins within the curve. CONCLUSIONS: The proposed criteria contributed to the harmonization of reference interval calculation between users of the Bhattacharya indirect method Spreadsheet.

Basalt Fiber Composites with Reduced Thermal Expansion for Additive Manufacturing.

Fused filament fabrication (FFF) is gaining attention as an efficient way to create parts and replacements on demand using thermoplastics. This technology requires the development of new materials with a reliable printability that satisfies the requirement of final parts. In this context, a series of composites based on acrylonitrile styrene acrylate (ASA) reinforced with basalt fiber (BF) are reported in this work. First, several surface modification treatments are applied onto the BF to increase their compatibility with the ASA matrix. Then, once the best treatment is identified, the mechanical properties, coefficient of thermal expansion (CTE) and warping distortion of the different specimens designed and prepared by FFF are studied. It was found that the silanized BF is appropriate for an adequate printing, obtaining composites with higher stiffness, tensile strength, low CTE and a significant reduction in part distortion. These composites are of potential interest in the design and manufacturing of final products by FFF, as they show much lower CTE values than pure ASA, which is essential to successfully fabricate large objects using this technique.

3D Bioprinted Hydrogel Microfluidic Devices for Parallel Drug Screening.

Conventional high-throughput screening (HTS) platforms suffer from the need for large cell volumes, high reagent consumption, significant assembly cost, and handling efforts. The assembly of three-dimensional (3D) bioprinted hydrogel-based microfluidic chips within platforms can address these problems. We present a continuous and seamless manufacturing approach to create a bioprinted microfluidic chips with a circular pattern scalable toward HTS platforms. Digital light processing 3D bioprinting is used to tune the local permeability of our chip, made of polyethylene glycol diacrylate and cell-laden gelatin methacryloyl, for creating predefined gradients of biochemical properties. We measured the flow-induced physical characteristics, the mass transport of drug agents, and the biological features of the proposed chip. We measured reactive oxygen species from the encapsulated cells through an integrated process and showed the capacity of the hydrogel-based chip for creating drug/agent gradients. This work introduces a chip design based on a hydrogel that can be changed and could be used for modern HTS platforms such as in vitro organoids.

Postischemic Neuroprotection of Aminoethoxydiphenyl Borate Associates Shortening of Peri-Infarct Depolarizations.

Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative stress are very promising approaches, but only a few compounds have reached the clinic with relatively good positive outcomes. The exploration of novel targets might overcome the lack of clinical translation of previous efficient preclinical neuroprotective treatments. In this study, we examined the neuroprotective properties of 2-aminoethoxydiphenyl borate (2-APB), a molecule that interferes with intracellular calcium dynamics by the antagonization of several channels and receptors. In a permanent model of cerebral ischemia, we showed that 2-APB reduces the extent of the damage and preserves the functionality of the cortical territory, as evaluated by somatosensory evoked potentials (SSEPs). While in this permanent ischemia model, the neuroprotective effect exerted by the antioxidant scavenger cholesteronitrone F2 was associated with a reduction in reactive oxygen species (ROS) and better neuronal survival in the penumbra, 2-APB did not modify the inflammatory response or decrease the content of ROS and was mostly associated with a shortening of peri-infarct depolarizations, which translated into better cerebral blood perfusion in the penumbra. Our study highlights the potential of 2-APB to target spreading depolarization events and their associated inverse hemodynamic changes, which mainly contribute to extension of the area of lesion in cerebrovascular pathologies.

Strategies for the Biofunctionalization of Straining Flow Spinning Regenerated Bombyx mori Fibers.

High-performance regenerated silkworm (Bombyx mori) silk fibers can be produced efficiently through the straining flow spinning (SFS) technique. In addition to an enhanced biocompatibility that results from the removal of contaminants during the processing of the material, regenerated silk fibers may be functionalized conveniently by using a range of different strategies. In this work, the possibility of implementing various functionalization techniques is explored, including the production of fluorescent fibers that may be tracked when implanted, the combination of the fibers with enzymes to yield fibers with catalytic properties, and the functionalization of the fibers with cell-adhesion motifs to modulate the adherence of different cell lineages to the material. When considered globally, all these techniques are a strong indication not only of the high versatility offered by the functionalization of regenerated fibers in terms of the different chemistries that can be employed, but also on the wide range of applications that can be covered with these functionalized fibers.

Methylene Blue functionalized carbon nanodots combined with different shape gold nanostructures for sensitive and selective SARS-CoV-2 sensing.

The development of DNA-sensing platforms based on new synthetized Methylene Blue functionalized carbon nanodots combined with different shape gold nanostructures (AuNs), as a new pathway to develop a selective and sensitive methodology for SARS-CoV-2 detection is presented. A mixture of gold nanoparticles and gold nanotriangles have been synthetized to modify disposable electrodes that act as an enhanced nanostructured electrochemical surface for DNA probe immobilization. On the other hand, modified carbon nanodots prepared a la carte to contain Methylene Blue (MB-CDs) are used as electrochemical indicators of the hybridization event. These MB-CDs, due to their structure, are able to interact differently with double and single-stranded DNA molecules. Based on this strategy, target sequences of the SARS-CoV-2 virus have been detected in a straightforward way and rapidly with a detection limit of 2.00 aM. Moreover, this platform allows the detection of the SARS-CoV-2 sequence in the presence of other viruses, and also a single nucleotide polymorphism (SNPs). The developed approach has been tested directly on RNA obtained from nasopharyngeal samples from COVID-19 patients, avoiding any amplification process. The results agree well with those obtained by RT-qPCR or reverse transcription quantitative polymerase chain reaction technique.

Preclinical Characterization of Antioxidant Quinolyl Nitrone QN23 as a New Candidate for the Treatment of Ischemic Stroke.

Nitrones are encouraging drug candidates for the treatment of oxidative stress-driven diseases such as acute ischemic stroke (AIS). In a previous study, we found a promising quinolylnitrone, QN23, which exerted a neuroprotective effect in neuronal cell cultures subjected to oxygen-glucose deprivation and in experimental models of cerebral ischemia. In this paper, we update the biological and pharmacological characterization of QN23. We describe the suitability of intravenous administration of QN23 to induce neuroprotection in transitory four-vessel occlusion (4VO) and middle cerebral artery occlusion (tMCAO) experimental models of brain ischemia by assessing neuronal death, apoptosis induction, and infarct area, as well as neurofunctional outcomes. QN23 significantly decreased the neuronal death and apoptosis induced by the ischemic episode in a dose-dependent manner and showed a therapeutic effect when administered up to 3 h after post-ischemic reperfusion onset, effects that remained 11 weeks after the ischemic episode. In addition, QN23 significantly reduced infarct volume, thus recovering the motor function in a tMCAO model. Remarkably, we assessed the antioxidant activity of QN23 in vivo using dihydroethidium as a molecular probe for radical species. Finally, we describe QN23 pharmacokinetic parameters. All these results pointing to QN23 as an interesting and promising preclinical candidate for the treatment of AIS.