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Although surgical management of peripheral nerve injuries (PNIs) has improved over time, autografts are still the current “gold standard” treatment for PNIs, which presents numerous limitations. In an attempt to improve natural biomaterial-based nerve guidance conduits (NGCs), chitosan (CHT), a derivative of the naturally occurring biopolymer chitin, has been explored for peripheral nerve regeneration (PNR). In addition to CHT, keratin has gained enormous attention as a biomaterial and tissue engineering scaffolding. In this study, biomimetic CHT/keratin membranes were produced using a solvent casting technique. These membranes were broadly characterized in terms of their surface topography and physicochemical properties, with techniques such as Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), contact angle, weight loss and water uptake measurements, Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). Biological in vitroassays were also performed, where a preliminary cytotoxicity screening with the L929 fibroblast cell line revealed that the membranes and respective materials are suitable for cell culture. In addition, Schwann cells, fibroblasts and endothelial cells were directly seeded in the membranes. Quantitative and qualitative assays revealed that the addition of keratin enhanced cell viablity and adhesion. Based on the encouraging in vitroresults, the in vivoangiogenic/antiangiogenic potential of CHT and CHT/keratin membranes was assessed, using an optimized chick embryo chorioallantoic membrane assay, where higher angiogenic responses were seen in keratin-enriched materials. Overall, the obtained results indicate the higher potential of CHT/keratin membranes for guided tissue regeneration applications in the field of PNR.

In this letter, we investigate the sum of independent but not identically distributed (i.n.i.d.) Fisher–Snedecor $\mathcal {F}$ variates. First, a novel closed-form expression is derived for the moment generating function of the instantaneous signal-to-noise ratio. Based on this, the corresponding probability density function and cumulative distribution function of the sum of i.n.i.d. Fisher–Snedecor $\mathcal {F}$ variates are derived, which are subsequently employed in the analysis of multiple branch maximal-ratio combining (MRC). Specifically, we investigate the impact of multipath and shadowed fading on the outage probability and outage capacity of MRC based receivers. In addition, we derive exact closed-form expressions for the average bit error rate of coherent binary modulation schemes followed by an asymptotic analysis which provides further insights into the effect of the system parameters on the overall performance.

It has been with great honor and responsibility that I have served as the Editor-in-Chief (EiC) of IEEE Communications Letters for the last four years (2019–2023). The role of EiC has become part of my everyday life and allowed me to work directly with a truly committed team of over 150 Editors, including Review Editors, Senior Editors, Area Editors, Expert Editors for invited papers, and Executive Editors. During my two terms as EiC, we handled more than 3000 manuscripts annually, which we processed rigorously and timely ensuring a turnaround time of no more than 40 days for more than 90% of submitted papers while reducing the number of papers reviewed beyond 50 days to just a handful. Despite the large number of papers and the short turnaround time, our Editors have secured high-quality reviews and spent a significant amount of time in justifying their editorial decisions for all handled papers. To ensure a better distribution of the editorial tasks, we have restructured the editorial board, by grouping the Editors into 13 thematic areas, each led by one Area Editor and one Senior Editor, who have been instrumental in ensuring coherence between the technical content of the papers reviewed and the technical scope of IEEE Communications Letters, as well as assisting the Review Editors in ensuring the highest quality and timeliness of the review process. We have introduced the role of Executive Editors, who worked daily with me in analyzing and assigning the submitted papers to the Review Editors. To promote some emerging areas, we have solicited invited papers from distinguished researchers, and we have introduced the role of Expert Editors for assisting me in the analysis of these papers. During the last four years, 46 invited 5-page papers were published in IEEE Communications Letters. To ensure an informed review process, we have introduced custom questions at the time of submission, which has allowed us to conduct a thorough analysis of all papers before initiating the review process. This allowed us to avoid cases of pre-publishing or plagiarism. To offer authors their preferred review process, we have given them the option to select two types of review processes: single-blind and double-blind. This has been well received by the authors and approximately 50% of the submitted papers are now reviewed according to the single-blind or double-blind peer-review process) Also, to better present the content of the journal, we have reorganized the table of contents by introducing thematic areas aligned with the structure of the editorial board) At present, the impact factor of the IEEE Communications Letters is the highest since the journal was established.

IMPORTANCE: Osimertinib mesylate is used globally to treat EGFR-mutant non–small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. OBJECTIVE: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. MAIN OUTCOMES AND MEASURES: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. RESULTS: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01). CONCLUSIONS AND RELEVANCE: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.

Background: Controlled drug delivery systems can maintain the concentration of drugs in the exact sites of the body within the optimum range and below the toxicity threshold, improving therapeutic efficacy and reducing toxicity. Mesostructured Cellular Foam (MCF) material is a new promising host for drug delivery systems due to high biocompatibility, in vivo biodegradability and low toxicity. Methods: Ketorolac-Tromethamine/MCF composite was synthesized. The material synthesis and loading of ketorolac-tromethamine into MCF pores were successful as shown by XRD, FTIR, TGA, TEM and textural analyses. Results: We obtained promising results for controlled drug release using the novel MCF material. The application of these materials in KETO release is innovative, achieving an initial high release rate and then maintaining a constant rate at high times. This allows keeping drug concentration within the range of therapeutic efficacy, being highly applicable for the treatment of diseases that need a rapid response. The release of KETO/MCF was compared with other containers of KETO (KETO/SBA-15) and commercial tablets. Conclusion: The best model to fit experimental data was Ritger-Peppas equation. Other models used in this work could not properly explain the controlled drug release of this material. The predominant release of KETO from MCF was non-Fickian diffusion.

This study aimed to evaluate the functional capacity and the behavior of inflammatory mediators in patients with stage I-IV chronic obstructive pulmonary disease in response to a pulmonary rehabilitation program (PRP). Both distance walked and maximal inspiratory pressure increased. The inflammatory markers showed varied behavior, with only soluble tumor necrosis factor receptor 1 levels reflecting improvement in inflammation after the PRP.

Fibrocartilage is a very peculiar type of tissue found in intervertebral disc and meniscus. It is characterized by its avascular nature and for the shear and compressive forces that it can be subjected to. The number of individuals affected by the degeneration of fibrocartilaginous tissues has been growing and the poor outcomes of current treatments have led to an increased interest in new alternative approaches. Therefore, the combination of reverse engineering with 3D printing has been extensively explored in order to produce patient-specific implants capable of improving the current clinical outcomes. This review outlines the recent advances achieved in the tissue engineering field, especially focusing on fibrocartilaginous tissue.

Rangelia vitaliiis the etiologic agent of canine rangeliosis, a severe piroplasmosis that affects domestic dogs in Brazil, Uruguay and Argentina. While R. vitaliiis one of the most pathogenic tick-borne pathogens for dogs in the world, its tick vector has remained unknown. The present study evaluated the vector competence of Rhipicephalus sanguineussensu lato (both tropical and temperate species), Amblyomma aureolatum, Amblyomma ovale, Amblyomma tigrinum,and Amblyomma sculptumfor R. vitalii.These six tick species were selected for the study because they comprise the main tick species infesting dogs within the distribution area of canine rangeliosis in South America. Acquisition feeding of the above six tick species was performed on domestic dogs showing clinical signs of canine rangeliosis, after being experimentally infected through intravenous inoculation or infestation with R. vitalii-infected ticks. Thereafter, engorged ticks were evaluated for transstadial and transovarial passages of R. vitaliithrough molecular analysis after molting or oviposition and egg hatching. The resultant ticks were evaluated for their competence to transmit R. vitaliito susceptible dogs. Among the six tick species, only A. aureolatumwas able to acquire and perpetuate R. vitaliiby transstadial and transovarial passages, as demonstrated by >5% infection rates of ticks after hatching or molting. When exposed to transmission feeding, only A. aureolatumticks were competent to transmit R. vitaliito dogs, which became severely ill, and the results confirmed by molecular methods and blood smear examination to have acquired rangeliosis. Results of the present study, coupled with epidemiological data, indicate that A. aureolatumis a natural vector of R. vitalii.Our results also indicate that R. vitaliiis the first Piroplasmorida agent to be transovarially transmitted in Amblyommaticks.

Despite widespread administration of programmed death receptor 1 (PD-1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) – infected patients since this population has largely been excluded from immunotherapy clinical trials.

In South America, early reports from more than 50 years ago incriminated Ornithodoros rudisas vector of Borrelia venezuelensis,an agent of tick-borne relapsing fever (TBRF). Herein we report the rediscovery of O. rudisby means of morphological, biological and molecular analyses, which also comprise the first report of this tick species in Brazil. Phylogenetic analysis using partial fragments of mitochondrial 16S rRNA gene suggested that O. rudisforms a monophyletic group with Ornithodoros erraticus. By using laboratory rodents as hosts, we isolated a relapsing fever Borreliafrom an infected O. rudisfemale. Phylogenetic analysis inferred from the rrs, flaB, and glpQgenes of Borreliaspp. placed the spirochete harbored by O. rudisclosely related to Borrelia turicatae.Until further genetic evidence is not obtained we are referring to this O. rudisspirochete as B. venezuelensis. This is the first in vitro isolation of a TBRF Borreliafrom South America. The presence of O. rudisin Brazil should not be overlooked, since this tick has been historically implicated in human cases of TBRF in Colombia, Panama, and Venezuela. This study provides new reports of O. rudisand B. venezuelensisafter decades of scientific silence on these agents.

This study was conducted to test the hypothesis that the inclusion of crude glycerin of up to 21% of DM in the diets of lambs will not compromise variables related to animal production or health. Forty-four uncastrated Santa Inês crossbreed lambs with an average age of 5 mo and a BW average of 23.9 ± 0.34 kg (mean ± SD) were distributed into four treatment groups (11 replicates per group) including 0%, 7%, 14%, or 21% crude glycerin on a DM basis. The inclusion of crude glycerin in the diets promoted a quadratic increase in DM (P= 0.018), CP (P= 0.004), and TDN (P= 0.017). There was a linear decrease (P< 0.001) in NDF and nonfibrous carbohydrate (NFC) intake caused by glycerin in the diets. There was a linear increase (P< 0.001) in ether extract (EE) intake. There was a linear reduction in NDF (P= 0.011) and NFC (P< 0.001) for effective consumption of the diets. There was a linear increase (P< 0.001) in EE effectively consumed by the lambs, and there were no differences in the CP that was effectively consumed (P= 0.267) by glycerin. Digestibility coefficients of DM, CP, NDF, NFC, and TDN presented a linear decrease in crude glycerin inclusion. The EE digestibility presented a linear increase. The inclusion of crude glycerin in the diets promoted a quadratic increase in final BW (P= 0.015), ADG (P< 0.001), and G:F ratio (P< 0.001). There was no effect (P> 0.05) of crude glycerin inclusion in the diets on time spent (%); number of events per day; duration of events (minutes) for feeding, rumination, and idling; number of chews per bolus; or total chewing time for the lambs. The inclusion of crude glycerin in the diets improved feeding efficiency of DM (P= 0.005) and NDF (P= 0.004). The rumination efficiency of DM (P< 0.001) and NDF (P< 0.001) presented a linear decrease. The total protein, albumin, globulin, albumin:globulin ratio, triglycerides, alanine aminotransferase levels, aspartate aminotransferase, and gamma glutamyl transferase serum concentrations did not differ (P> 0.05) through the addition of crude glycerin to the diets of the lambs. However, the crude glycerin in the diets led to a linear decrease in urea-N (P= 0.004) and glucose (P<0.001), as well as a linear increase in the cholesterol (P= 0.043) serum concentrations of the lambs. The recommended inclusion of crude glycerin is up to a 4.7% DM level because of improved performance growth without compromising feeding behavior and blood metabolites.

The aims of this study were to quantify the relationship between computed tomography (CT) size, volume, density, and roundness of lung adenocarcinomas (ACs) manifesting as pure ground-glass nodules (pGGNs) on CT images and to correlate these parameters with histologic features of invasiveness.

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncologypublish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

Background: Alzheimer's disease (AD) is defined as a progressive and irreversible neurodegenerative disorder, the onset of which is mainly characterized by decreased cognition, memory loss, and mental confusion. Objective: This study sought to quantify mRNA expression of the APBA2, INSR and IDE genes in brain samples from patients with AD and controls. Methods: We investigated the mRNA expression of the APBA2, INSR and IDE genes in 150 RNA samples from entorhinal cortex, auditory cortex, and the hippocampus of individuals with AD and elderly controls using real time PCR. APOE genotypes were determined by PCR-RFLP. Results: When the total brain samples were analyzed collectively, a decrease in IDE gene expression was found in AD patients relative to healthy elderly controls. However, when the samples were analyzed separately according to the region of the brain, there was a significant upregulation of INSR expression in the hippocampus and the entorhinal cortex in the AD patient group. We did not observe any statistical differences when gene expression was compared in the different regions of the brain of AD patients. When the E4 allele of apolipoprotein-E was considered in AD patients, the presence of this allele was found to be associated with decreased APBA2 gene expression. The same analysis using the INSR and IDE genes showed no significant statistical differences. Conclusion: These results support the hypothesis that APBA2, IDE, and particularly INSR gene expression in different areas of Alzheimer’s patient’s brains could represent new markers for use in clinical diagnoses in the near future.

Targeted somatic genomic analysis (EGFR, anaplastic lymphoma receptor tyrosine kinase gene [ALK],and ROS1) and programmed death ligand 1 (PD-L1) tumor proportion score (TPS) determined by immunohistochemistry (IHC) are used for selection of first-line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported.

This study focuses on the importance of the feed volume as an operational parameter for improving the performance of a cyclically fed glycerol-based microbial fuel cell. Experiments varying the daily feed volume from 10 to 50 mL for a 240 mL anode evidences that the electrochemical performance, Chemical Oxygen Demand (COD) and nitrogen and phosphorous removal is affected, in addition to the Coulombic efficiency (CE) and the kinetics of the glycerol biodegradation. A feed volume of 32 mL (hydraulic retention time (HRT) of 7.5 d) is shown to be the most effective for maximising the cell performance and COD removal. Longer HRTs reduce the organic loading rate, thereby reducing the cell performance due to the rapid depletion of the substrate, whereas shorter HRTs favor the development of non-exoelectrogenous bacteria, which reduces the CE and electrochemical performance with less effective COD removal. A final product analysis reveals that formic acid is the main product formed as a consequence of the microbiological degradation of glycerol.

Electrothermal vaporization (ETV)-inductively coupled plasma optical emission spectrometry (ICP OES) is proposed for multielement determination in powdered medicinal plants. Simultaneous determination of As, Cd, Cr, Cu, Mn, Ni, Pb and Zn was performed in 10 herbs consumed in Brazil. Heating of the ETV system and the influence of carrier gas flow rate, modifier gas (Freon R12, CCl2F2) flow rate and sample mass were evaluated and adjusted to obtain the best signal/noise ratio. Temperatures of 300 °C and 1800 °C were used for pyrolysis and vaporization, respectively. Freon has a strong influence on the pyrolysis and vaporization temperatures and the sensitivity. Although the partial elimination of the sample matrix and Freon can act to minimize matrix effects, standard addition calibration was necessary for direct element determination in solid samples. The accuracy of ETV-ICP OES measurements was evaluated by analysing two certified reference materials (NIST 1515 – Apple Leaves and NIST 1574 – Peach Leaves), and the comparison of results obtained by solution nebulization ICP OES (NEB-ICP OES) for acid decomposed samples. The results were in good agreement (t-test at the 95% confidence level) with certified values and those obtained by NEB-ICP OES. Precision was better than 20%, considering the standard deviation of five replicates, and limits of detection and quantification varied from 0.01 to 0.48 and 0.03 to 1.60 μg g−1, respectively. The proposed method allows the simultaneous determination of As, Cd, Cr, Cu, Mn, Ni, Pb and Zn in medicinal plants in less than 5 min, including the sample preparation step.

ALKinternal deletions of nonkinase domain exons occur in 0.01% of lung cancers with ALKgenomic aberrations. We report a lung adenocarcinoma with a previously undescribed somatic ALKdeletion of exons 2 to 19 with dramatic and sustained (>23 mo) response to alectinib. Our and other reported cases with ALKnonkinase domain deletions (between introns and exons 1–19) can display positive results in nonsequencing-based lung cancer diagnostic tests (such as immunohistochemistry) used to screen for more common ALKrearrangements. This case report emphasizes that “ALK-driven” lung cancers should be expanded to encompass those harboring not only ALKrearrangements with other genes but also ALKnonkinase domain deletions.