Rational Design and Multicomponent Synthesis of Lipid-Peptoid Nanocomposites towards a Customized Drug Delivery System Assembly.

Nanotechnology has assumed a significant role over the last decade in the development of various technologies applied to health sciences. This becomes even more evident with its application in controlled drug delivery systems. In this context, peptoids are a promising class of compounds for application as nanocarriers in drug delivery systems. These compounds can be obtained efficiently and with highly functionalized structural diversity via the Ugi 4-component reaction (U-4CR). Herein, we report the design of the process control strategy for the future development of lipid-peptoid-based customized drug delivery system assemblies. Over 20 lipid-peptoid nanocomposites were synthesized via the U-4CR in good to excellent yields. These products were successfully submitted to the nanoparticle formation by the emulsification-evaporation process from lipophilic solution and analyzed via Dynamic Light Scattering (DLS). Several molecules generated nanoparticles with a size ≤200 nm, making them good candidates for drug delivery systems, such as in cancer treatment.

Atherosclerotic-Derived Endothelial Cell Response Conducted by Titanium Oxide Nanotubes.

Atherosclerosis lesions are described as the formation of an occlusive wall-vessel plaque that can exacerbate infarctions, strokes, and even death. Furthermore, atherosclerosis damages the endothelium integrity, avoiding proper regeneration after stent implantation. Therefore, we investigate the beneficial effects of TiO2 nanotubes (NTs) in promoting the initial response of detrimental human atherosclerotic-derived endothelial cells (AThEC). We synthesized and characterized NTs on Ti6Al4V by anodization. We isolated AThEC and tested the adhesion long-lasting proliferation activity, and the modulation of focal adhesions conducted on the materials. Moreover, ultrastructural cell-surface contact at the nanoscale and membrane roughness were evaluated to explain the results. Our findings depicted improved filopodia and focal adhesions stimulated by the NTs. Similarly, the NTs harbored long-lasting proliferative metabolism after 5 days, explained by overcoming cell-contact interactions at the nanoscale. Furthermore, the senescent activity detected in the AThEC could be mitigated by the modified membrane roughness and cellular stretch orchestrated by the NTs. Importantly, the NTs stimulate the initial endothelial anchorage and metabolic recovery required to regenerate the endothelial monolayer. Despite the dysfunctional status of the AThEC, our study brings new evidence for the potential application of nano-configured biomaterials for innovation in stent technologies.

Lenalidomide-dexamethasone versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A randomized, open-label study.

BACKGROUND: Smoldering multiple myeloma (SMM) is a heterogeneous disease in terms of progression to myeloma (MM), but its standard of care continues to be observation. METHODS: The QuiRedex phase 3 trial initiated in 2007 included 119 high-risk patients with SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide [Rd], 25 mg on days 1-21 plus dexamethasone, 20 mg on days 1-4 and 12-15), followed by maintenance (R, 10 mg on days 1-21) for up to 2 years. The primary end-point was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363). FINDINGS: After a median follow-up time of 12.5 years (range: 10.4-13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18-0.44, p < 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96). INTERPRETATION: This analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS. FUNDING: Pethema (Spanish Program for the Treatment of Hematologic Diseases), Spain.

Combining chemometric and phytochemical tools to isolate and characterize activity of Vismia gracilis compounds against Aedes aegypti.

Vismia gracilis extracts were tested against Aedes aegypti to assess mortality and behavioural effects. The leaf hexanic extract (L-Hex) presented increased larvicidal activity with exposure period: LC50 46.48 µg/mL (24 h) and LC50 20.57 µg/mL (48 h). Eight compounds were annotated/isolated from the L-Hex active extract, 4 benzophenones and 4 anthraquinones. Considering chemometric findings, the benzophenone moiety, tested as the commercial benzophenone, promoted larval mortality (LC50 16.35 µg/mL). Both the L-Hex extract and benzophenone induced intestinal damage in larvae. Benzophenone also promoted toxicity and behavioural effects in female adults. These findings highlighted the potential use of this class of compounds for developing vector-control products.

Azadirachta indica Leaf Extract as Green Corrosion Inhibitor for Reinforced Concrete Structures: Corrosion Effectiveness against Commercial Corrosion Inhibitors and Concrete Integrity.

The construction industry has extensively demanded novel green inhibition strategies for the conservation and protection of carbon steel-reinforced concrete structures. For the first time, the effect of Azadirachta indica leaf extract (Neem) as a potential corrosion inhibitor of carbon steel in reinforced concrete under corrosion in saline simulated media was evaluated. To assess the corrosion inhibition behavior of the Neem natural organic extract, three inorganic commercial inhibitors were tested to compare following the criteria established by Stratful for half-cell potential under a simulated chloride environment. Moreover, the effect of concrete integrity by the Neem treatment was recorded after different temperature conditions, slump, weight alteration, air content, compressive strength, and chloride-ions penetration. The results suggested that the Neem treatments did not alter the concrete integrity and the physicochemical parameters. We reached a promoted long-term corrosion protection of 95% after 182 days of evaluation. Thus far, our current results open up a new promising "green" road to the conservation of carbon steel in reinforced concrete for the construction industry.

Promotion of Surgical Masks Antimicrobial Activity by Disinfection and Impregnation with Disinfectant Silver Nanoparticles.

BACKGROUND: The COVID-19 pandemic is requesting highly effective protective personnel equipment, mainly for healthcare professionals. However, the current demand has exceeded the supply chain and, consequently, shortage of essential medical materials, such as surgical masks. Due to these alarming limitations, it is crucial to develop effective means of disinfection, reusing, and thereby applying antimicrobial shielding protection to the clinical supplies. PURPOSE: Therefore, in this work, we developed a novel, economical, and straightforward approach to promote antimicrobial activity to surgical masks by impregnating silver nanoparticles (AgNPs). METHODS: Our strategy consisted of fabricating a new alcohol disinfectant formulation combining special surfactants and AgNPs, which is demonstrated to be extensively effective against a broad number of microbial surrogates of SARS-CoV-2. RESULTS: The present nano-formula reported a superior microbial reduction of 99.999% against a wide number of microorganisms. Furthermore, the enveloped H5N1 virus was wholly inactivated after 15 min of disinfection. Far more attractive, the current method for reusing surgical masks did not show outcomes of detrimental amendments, suggesting that the protocol does not alter the filtration effectiveness. CONCLUSION: The nano-disinfectant provides a valuable strategy for effective decontamination, reuse, and even antimicrobial promotion to surgical masks for frontline clinical personnel.

Structure-activity relationship of diameter controlled Ag@Cu nanoparticles in broad-spectrum antibacterial mechanism.

Current outbreaks associated with drug-resistant clinical strains are demanding for the development of broad-spectrum antibacterial agents. The bactericidal materials should be eco-friendly, economical and effective to suppress bacterial growth. Thus, in this work, diameter controlled spherical Cucore-Agshell nanoparticles (Ag@CuNPs) with diameter ranging from 70 to 100 nm by one-step co-reduction approach were designed and synthesized. The Ag@CuNPs were homogenous, stable, and positively charged. The 70 nm Ag@CuNPs showed a consistent and regular Ag shielding. We observed the 100 nm Ag@CuNPs achieved symmetrical doped Ag clusters on the Cu core surface. We used Gram-positive and Gram-negative models strains to test the wide-spectrum antibacterial activity. The Ag@CuNPs showed detrimental microbial viability in a dose-dependent manner; however, 70 nm Ag@CuNPs were superior to those of 100 nm Ag@CuNPs. Initially, Ag@CuNPs attached and translocated the membrane surface resulting in bacterial eradication. Our analyses exhibited that antibacterial mechanism was not governed by the bacterial genre, nonetheless, by cell type, morphology, growing ability and the NPs uptake capability. The Ag@CuNPs were highly tolerated by human fibroblasts, mainly by the use of starch as glucosidic capper and stabilizer, suggesting optimal biocompatibility and activity. The Ag@CuNPs open up a novel platform to study the potential action of bimetallic nanoparticles and their molecular role for biomedical, clinical, hospital and industrial-chemical applications.

Neotropical carnivores: a data set on carnivore distribution in the Neotropics

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non‐detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non‐governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peerreviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non‐detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio‐temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other largescale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data.

Interaction Between Cobalt Ferrite Nanoparticles and Aspergillus niger Spores.

The immobilization of microorganisms has been reported as an alternative to improve the efficiency of processes such as fermentation, anaerobic digestion, bioadsorption, and many others. Since the kinetics of bioprocesses are governed by the adsorbent/adsorbate interaction, it is important to know the mechanisms of interaction between biological materials and supports. This could help to define optimal operating conditions. In this research, the fungus that produces the cellulases, was selected, and the characterization of the interaction between fungal spores and cobalt ferrite magnetic nanoparticles, was performed. In order to select a fungal strain produces cellulase enzymes, a qualitative Congo Red test was carried out with a culture medium rich in carboxymethylcellulose. From five strains, Aspergillus niger was selected. Chitosan coated cobalt ferrite magnetic nanoparticles (CoMNP-C) were synthesized by single-step co-precipitation. The nano-size of CoMNP-C was demonstrated by XRD. The presence of a high content of amino groups (0.144 mM g-1) was observed, that could have an important role in the interaction between nanoparticles and spores. Adsorption kinetic studies were carried out. The pseudo-equilibrium time was estimated as 90 min. Spores adsorption isotherm was obtained with 3.45 mg of synthesized material at 30 °C. It was found that the adsorption of spores may be described by both models (Langmuir and Freundlich), suggesting a homogeneous surface of the nanoparticles and a multilayer adsorption phenomenon. These results can have transcendence in multiple applications based on the studied process.

A Mild, Fast, and Scalable Synthesis of Substituted α-Acyloxy Ketones via Multicomponent Reaction Using a Continuous Flow Approach.

A continuous flow approach for the synthesis of α-acyloxy ketone derivatives from the corresponding arylglyoxals, isocyanides, and carboxylic acids is described. The target products were obtained in excellent yields in short residence times and with high purities via the first transcription of the microwave-to-flow paradigm to the isocyanide-based Passerini reaction. Furthermore, this methodology allowed a 10-fold scale-up using the same experimental conditions initially established.

Estimulación cerebral profunda en pacientes parkinsonianos con intolerancia a levodopa / Deep brain stimulation in parkinsonian patients with dopa intolerance

La estimulacion cerebral profunda (ECP) es un tratamiento eficaz para pacientes con enfermedad de Parkinson con complicaciones motoras. El elemento más importante que predice la respuesta a la ECP es la respuesta a la levodopa. Mostramos dos casos de pacientes con enfermedad de Parkinson de comienzo precoz con intolerancia severa a la levodopa y excelente respuesta a ECP. La ECP puede ser una alternativa en pacientes parkinsonianos con intolerancia a la levodopa siempre que la respuesta a apomorfina sea positiva

Deep brain stimulation (DBS) is at present, a useful treatment for patients with advanced Parkinson's disease and motor complications. The crucial step toward consistent DBS outcomes remains careful patient selection; several conditions must be fulfilled including excellent levo dopa response. We report two cases of early onset Parkinson's disease with severe intolerance to levo dopa but excellent and sustained response to DBS. DBS can be a useful alternative for parkinsonian patients with severe intolerance to levo dopa, provided a positive acute response to levo dopa or apomorphine is obtained

[Deep brain stimulation in parkinsonian patients with dopa intolerance]. / Estimulación cerebral profunda en pacientes parkinsonianos con intolerancia a levodopa.

Deep brain stimulation (DBS) is at present, a useful treatment for patients with advanced Parkinson's disease and motor complications. The crucial step toward consistent DBS outcomes remains careful patient selection; several conditions must be fulfilled including excellent levo dopa response. We report two cases of early onset Parkinson's disease with severe intolerance to levo dopa but excellent and sustained response to DBS. DBS can be a useful alternative for parkinsonian patients with severe intolerance to levo dopa, provided a positive acute response to levo dopa or apomorphine is obtained.

Hormonal response recovery after long-term androgen deprivation therapy in patients with prostate cancer.

OBJECTIVE: The aim of this study was to evaluate hormonal recovery after cessation of androgen deprivation therapy (ADT) in a group of elderly prostate cancer patients. MATERIALS AND METHODS: Forty patients with locally advanced or metastatic prostate cancer, with a mean age of 71.5 years [95% confidence interval (CI) 69.1-73.9], were treated with ADT for a mean duration of 74.6 months (95% CI 59.7-89.5 months). Mean follow-up time after ADT cessation was 36.5 months (95% CI 30.6-42.3 months). Serum testosterone and luteinizing hormone (LH) were determined at 6 month intervals after ADT cessation. RESULTS: After 18 months of follow-up, all patients had recovered normal LH levels, while 38% of patients still presented castration levels of testosterone (< 50 ng/dl). A multivariate analysis was performed to find factors related to testosterone recovery (testosterone >50 ng/dl). Neither age at start of ADT nor clinical stage reached statistical significance. Only time under ADT was correlated with testosterone recovery (p = .031). Kaplan-Meier curves were obtained. Mean time for testosterone recovery was 14.5 months (95% CI 6.5-22.6 months) in patients treated with ADT for less than 60 months compared to 29.3 months (95% CI 19.6-39.1 months) in patients treated with ADT for more than 60 months (log-rank p = .029). CONCLUSIONS: Age did not correlate with testosterone recovery in a group of elderly prostate cancer patients in whom ADT was stopped. Testosterone recovery after ADT cessation was significantly correlated with time under ADT treatment. Significant implications related to economic aspects of the dosage schedule may be considered.

Identification of somatic gene mutations in penile squamous cell carcinoma.

There is a lack of studies on somatic gene mutations and cell signaling driving penile carcinogenesis. Our objective was to analyze somatic mutations in genes downstream of EGFR in penile squamous cell carcinomas, especially the mTOR and RAS/MAPK pathways. We retrospectively analyzed somatic mutations in 10 in situ and 65 invasive penile squamous cell carcinomas by using Sequenom's Mass Spectrometry iPlex Technology and Oncocarta v1.0 Panel. The DNA was extracted from FFPE blocks and we identified somatic missense mutations in three in situ tumors and in 19 invasive tumors, mostly in PIK3CA, KRAS, HRAS, NRAS, and PDGFA genes. Somatic mutations in the PIK3CA gene or RAS family genes were neither associated with tumor grade, stage or outcome, and were equally often identified in hrHPV positive and in hrHPV negative tumors that showed no p53 expression. Mutations in PIK3CA, KRAS, and HRAS are frequent in penile squamous cell carcinoma and likely play a role in the development of p53-negative tumors. Although the presence of these mutations does not seem to correlate with tumoral behavior or outcome, they could be biomarkers of treatment failure with anti-EGFR mAb in patients with penile squamous cell carcinoma.

Normalized medical information visualization.

A new mark-up programming language is introduced in order to facilitate and improve the visualization of ISO/EN 13606 dual model-based normalized medical information. This is the first time that visualization of normalized medical information is addressed and the programming language is intended to be used by medical non-IT professionals.

A sequential Ugi multicomponent/Cu-catalyzed azide-alkyne cycloaddition approach for the continuous flow generation of cyclic peptoids.

The development of a continuous flow multistep strategy for the synthesis of linear peptoids and their subsequent macrocyclization via Click chemistry is described. The central transformation of this process is an Ugi four-component reaction generating the peptidomimetic core structure. In order to avoid exposure to the often toxic and malodorous isocyanide building blocks, the continuous approach was telescoped by the dehydration of the corresponding formamide. In a concurrent operation, the highly energetic azide moiety required for the subsequent intramolecular copper-catalyzed azide-alkyne cycloaddition (Click reaction) was installed by nucleophilic substitution from a bromide precursor. All steps yielding to the linear core structures can be conveniently coupled without the need for purification steps resulting in a single process generating the desired peptidomimetics in good to excellent yields within a 25 min reaction time. The following macrocyclization was realized in a coil reactor made of copper without any additional additive. A careful process intensification study demonstrated that this transformation occurs quantitatively within 25 min at 140 °C. Depending on the resulting ring strain, either a dimeric or a monomeric form of the cyclic product was obtained.

Effects of holmium laser enucleation of the prostate on sexual function.

OBJECTIVE: To evaluate the effects of holmium laser enucleation of the prostate (HoLEP) on sexual function. METHODS: A retrospective analysis of 202 sexually active patients who underwent HoLEP was performed. Patients were assessed at baseline and 3 and 12 months post-HoLEP. Evaluations included uroflowmetry and symptom questionnaires (five-item version of the International Index of Erectile Function [IIEF-5], ICIQ-male sexual matters associated with LUTS [ICIQ-MLUTSsex], American Urological Association symptom score [AUA-SS], and single-question quality of life [QoL] score). Nonparametric, Fisher's exact, and chi-squared tests were used to assess changes from baseline and to identify risk factors, if any, associated with deterioration of sexual function after surgery. RESULTS: No significant differences were found between the preoperative and postoperative scores on the questionnaires that evaluated erection quality. However, 6.9% and 12.4% of the patients reported an increase or a reduction, respectively, of greater than five points in total IIEF-5 score. The reduction in IIEF-5 score was statistically significant only in the subgroup of patients without preoperative erectile dysfunction (ED). No preoperative characteristics and no parameters related to the surgery or postoperative outcome were significantly associated with the impairment of erection quality after surgery. In fact, neither capsular perforation nor the total laser energy used during the procedure affected erections. Loss of antegrade ejaculation was found in 70.3% of patients, while 21% reported a reduction in semen quantity. However, concern regarding ED or ejaculatory dysfunctions decreased with surgery. CONCLUSIONS: Although erectile function was not altered in the vast majority of patients after HoLEP, patients without preoperative ED displayed a relatively small, but still significant, negative effect on erections. The overwhelming majority of patients suffered from retrograde ejaculation after surgery.

Service for the Pseudonymization of Electronic Healthcare Records Based on ISO/EN 13606 for the Secondary Use of Information.

The availability of electronic health data favors scientific advance through the creation of repositories for secondary use. Data anonymization is a mandatory step to comply with current legislation. A service for the pseudonymization of electronic healthcare record (EHR) extracts aimed at facilitating the exchange of clinical information for secondary use in compliance with legislation on data protection is presented. According to ISO/TS 25237, pseudonymization is a particular type of anonymization. This tool performs the anonymizations by maintaining three quasi-identifiers (gender, date of birth, and place of residence) with a degree of specification selected by the user. The developed system is based on the ISO/EN 13606 norm using its characteristics specifically favorable for anonymization. The service is made up of two independent modules: the demographic server and the pseudonymizing module. The demographic server supports the permanent storage of the demographic entities and the management of the identifiers. The pseudonymizing module anonymizes the ISO/EN 13606 extracts. The pseudonymizing process consists of four phases: the storage of the demographic information included in the extract, the substitution of the identifiers, the elimination of the demographic information of the extract, and the elimination of key data in free-text fields. The described pseudonymizing system was used in three telemedicine research projects with satisfactory results. A problem was detected with the type of data in a demographic data field and a proposal for modification was prepared for the group in charge of the drawing up and revision of the ISO/EN 13606 norm.

Envisioning patient safety in Telehealth: a research perspective.

This article explores the need for research into patient safety in large-scale Telehealth systems faced with the perspective of its development extended to healthcare systems. Telehealth systems give rise to significant advantages in improving the quality of healthcare services as well as bringing about the possibility of new types of risk. A theoretical framework is proposed for patient safety for its approach as an emerging property in complex socio-technical systems (CSTS) and their modelling in layers. As regards this framework, the differential characteristic Telehealth elements of the system have been identified, with a greater emphasis on the level of Telehealth system and its typical subsystems. The bases of the analysis are based on references in the literature and the experience accumulated by the researchers in the area. In particular, a case describing an example of Telehealth to control patients undergoing treatment with oral anticoagulants is used. As a result, a series of areas of research into and topics regarding Telehealth patient safety are proposed to cover the detectable gaps. Both the theoretical and practical implications of the study are discussed and future perspectives are reflected on.

Heart failure in primary care: co-morbidity and utilization of health care resources.

BACKGROUND: In order to ensure proper management of primary care (PC) services, the efficiency of the health professionals tasked with such services must be known. Patients with heart failure (HF) are characterized by advanced age, high co-morbidity and high resource utilization. OBJECTIVE: To ascertain PC resource utilization by HF patients and variability in the management of such patients by GPs. METHODS: Descriptive, cross-sectional study targeting a population attended by 129 GPs over the course of 1 year. All patients with diagnosis of HF in their clinical histories were included, classified using the Adjusted Clinical Group system and then grouped into six resource utilization bands (RUBs). Resource utilization and Efficiency Index were both calculated. RESULTS: One hundred per cent of patients with HF were ranked in RUBs 3, 4 and 5. The highest GP visit rate was 20 and the lowest in excess of 10 visits per year. Prescription drug costs for these patients ranged from €885 to €1422 per patient per year. Health professional efficiency varied notably, even after adjustment for co-morbidity (Efficiency Index Variation Ratio of 28.27 for visits and 404.29 for prescription drug cost). CONCLUSIONS: Patients with HF register a high utilization of resources, and there is great variability in the management of such patients by health professionals, which cannot be accounted for by the degree of case complexity.