Electrosprayed Minocycline-loaded PLGA Microparticles for the Treatment of Glioblastoma

Background: Around 12,340 patients in the US are diagnosed with glioblastoma multiforme (GBM) yearly, and despite the current treatment options, such as chemotherapy, radiotherapy, surgical resection, or a combination of them, the median survival is only about 15 months after initial diagnosis. Minocycline, a tetracycline antibiotic, has shown to inhibit U87 glioblastoma cell death and inhibit angiogenesis, or the creation of new blood vessels as is often needed by the tumor to grow. The utilization of biomaterials such as poly lactic-co-glycolic acid (PLGA) can better sustain the release and bioactivity of loaded drugs. The use of polyethylene glycol (PEG), a hydrophilic polymer, may improve the encapsulation of minocycline into the PLGA microparticles, given its hydrophilic nature. Electrospraying may be a promising method to fabricate drug loaded PLGA microparticles with high drug loading and loading efficiency. Therefore, the objective of this project was to develop electrosprayed minocycline-loaded PLGA microparticles for the treatment of GBM. Methods: Minocycline-loaded PLGA microparticles were fabricated through electrospraying utilizing an 18 cm needle-tip to glass plate distance, 0.9 ml/hr flowrate, and 14 kV voltage. The solution consisted of 1 ml of chloroform as the solvent and 70 mg of PLGA as the polymer with different minocycline amounts and with or without polyethylene glycol (PEG). The amount of drug loaded into the microparticles was determined by dissolving the microparticles in 1 mL of dimethylsulfoxide and then measuring the absorbance of minocycline at 350 nm. Release kinetics studies were performed by placing the microparticles in phosphate-buffered saline and reading minocycline absorbance of the supernatant at various timepoint. Scanning Electron Microscopy (SEM) was used to determine size and morphology of the minocycline-loaded PLGA microparticles. Results: The amount of drug loading and loading efficiency increased with the addition of PEG (3.23 ± 0.29 vs. 4.02 ± 0.34 and 49.40 ± 4.49 vs. 64.30 ± 5.47%, respectively) and the utilization of higher amount of drug (4.02 ± 0.34 vs. 9.93 ± 0.64 and 64.30 ± 5.47 vs. 70.76 ± 4.57%, respectively). The release kinetics study demonstrated that the different microparticles experienced a burst release within the first hour (67-80%). The microparticles were spherical in shape and ranged between 4-11 μm in size. The addition of PEG resulted in the aggregation of the microparticles, as observed in SEM imaging. Conclusions: This study demonstrated that electrosprayed minocycline-loaded PLGA microparticles can be successfully fabricated with high drug loading and loading efficiency and have a spherical shape within the micron size range. PEG was able to increase drug loading of the lipophilic drug by increasing the solubility of the drug in the polymer/chloroform solution. However, the utilization of PEG affected the collection of the particles and therefore, further optimization of the electrospraying parameters needs to be done to improve the collection of non-aggregated microparticles. In addition, given their burst release of minocycline, the microparticles may need to be further encapsulated in a scaffold or depot to prolong their release of drug

Relatively low-temperature processing and its impact on device performance and reliability

Non-silicon, large-area/flexible electronics for the internet of things (IoT) has acquired substantial attention in recent years. Key electron devices to enable this technology include metal-oxide-semiconductor field effect transistors (MOSFETs), where ultra-thin and/or low-dimensional (i.e., 2D to a few layers) semiconductor materials may be required, like those found in thin-film transistors (TFTs) and transition metal dichalcogenide (TMD) FETs [1,2]. Whether TFT or TMDFET, a relatively low-temperature process commensurate with large-area/flex applications to enable large (i.e., greater than 300 mm) and/or flexible substrate fabrication is required. Furthermore, TMD materials may be implemented as the channel semiconductor to function as an ultra-thin body to mitigate short channel effects and extend further scaling as the future progresses in CMOS scaling. In addition, the gate dielectric insulator is another vital component of any MOSFET that requires investigation as part of the MOS stack in these types of transistors. Lastly, semiconductor materials mentioned herein do not have a universally accepted way to introduce dopants to form sources and drains. Thus, metal-semiconductor contacts are employed where the interface region of the contact plays a critical role in determining the conductivity/resistivity of the contact. Moreover, how the metal-semiconductor interface are formed also impacts the quality of the contact. Therefore, exploration of low-temperature processing, interfaces, and their impact on device performance and reliability will be critical to eventual implementation in future technologies. To ascertain the impact of low-temperature fabrication and critical interfaces, several process approaches and electrical characterization methods were employed [1-6]. In one case, for a TMD FET contact study, an oxygen plasma exposure in the contact region on MoS2 (a TMD material) is done prior to titanium deposition. The results demonstrate that contaminants and photoresist residue that still reside after development can noticeably impact electrical performance (Fig. 1). The O2 plasma removes the residue present at the surface of MoS2 without the use of a high temperature anneal, and subsequently improves the device performance significantly (Fig. 1) [1]. In another case, for a MOS-based TFT study, an investigation of low-temperature (\u3e 115°C) deposited zinc-based semiconductors was executed (Fig. 2). For ZnO and IGZO, saturation mobilities of 14.4 and 8.4 cm2/V-s, along with threshold voltages of 2.2 V and 2.0 V were obtained, respectively, demonstrating robust devices that also have an on/off ratio \u3e 108, with IOFF lower than 10-12 A. Furthermore, a hot carrier stress methodology demonstrated threshold voltage (VTH) shifts of 0.4 V and 1.8 V for ZnO and IGZO, respectively, after stress (Fig. 2) [2]. Continued research is required to ascertain the electrically active defects responsible for the VTH shift. Please click Additional Files below to see the full abstract

The effect of Brahman genes on body temperature plasticity of heifers on pasture under heat stress

Bos taurus indicus cattle have the superior ability for the regulation of body temperature during heat stress due to a number of physiological and cellular level adaptive traits. The objectives of this study were to quantify the change in body temperature in heifers with various proportions of Brahman genes per unit increase in heat stress as measured by temperature-humidity index (THI) and to assess how different breed groups responded to varying intensity and duration of heat stress. A total of 299 two-yr-old heifers from six breed groups ranging from 100% Angus to 100% Brahman were evaluated under hot and humid conditions during 2017 and 2018 summer days. Two strategies were used to estimate the plasticity in body temperature of breed groups in response to environmental challenges: 1) a random regression mixed model was used to estimate reaction norm parameters for each breed group in response to a specified environmental heat stress and 2) a repeated measures mixed model was used to evaluate the response to different environmental heat loads. The reaction norm model estimated an intercept and slope measuring the change in body temperature per unit increase in THI environmental heat stress for different breed groups of animals and allowed the identification of genotypes which are robust, with low slope values indicative of animals that are able to maintain normal body temperature across a range of environments. The repeated measures mixed model showed that Brahman cattle have an advantage under moderate or high heat stress conditions but both Angus and Brahman breed groups are greatly affected when heat stress is severe. A critical factor appears to be the opportunity to cool down during the night hours more than the number of hours with extreme THI. With heat stress conditions predicted to intensify and expand into currently temperate zones, developing effective strategies to ensure sustainable beef production systems are imperative. Effective strategies will require the identification of the genes conferring the superior thermotolerance in Brahman cattle.United States Department of Agriculture (USDA) (017-67007-26143)Florida Agricultural Experiment Station Hatch (FLA-ANS-005548

Optimizing the linearity in high-speed photodiodes

Analog photonic links require high-fidelity, high-speed optical-to-electrical conversion for applications such as radio-over-fiber, synchronization at kilometer-scale facilities, and low-noise electronic signal generation. Photodetector nonlinearity is a particularly vexing problem, causing signal distortion and excess noise, especially in systems utilizing ultrashort optical pulses. Here we show that photodetectors designed for high power handling and high linearity can perform optical-to-electrical conversion of ultrashort optical pulses with unprecedented linearity over a large photocurrent range. We also show that the broadband, complex impedance of the circuit following the photodiode modifies the linearity significantly. By externally manipulating the circuit impedance, we extend the detector's linear range to higher photocurrents, with over 50 dB rejection of amplitude-to-phase conversion for photocurrents up to 40 mA. This represents a 1000-fold improvement over state-of-the-art photodiodes and significantly extends the attainable microwave power by a factor of four. As such, we eliminate the long-standing requirement in ultrashort pulse detection of precise tuning of the photodiode's operating parameters (average photocurrent, bias voltage or temperature) to coincide with a nonlinearity minimum. These results should also apply more generally to reduce nonlinear distortion in a range of other microwave photonics applications

Adherence to antiretroviral therapy and the associated factors among people living with HIV/AIDS in Northern Peru : a cross-sectional study

Altres ajuts: This study was partially funded by a research Grant from the Fundació Autònoma Solidària (Resolució Convocatòria FSXXXIII-Peru); and the Oficina de Investigación y Creatividad Intelectual from the Universidad María Auxiliadora (OICI-001-2017).There are approximately 72,000 people living with HIV/AIDS (PLHIV) in Peru. Non-adherence to antiretroviral therapy (ART) is the most important factor for therapeutic failure and the development of resistance. Peru has achieved moderate progress in meeting the 90-90-90 targets, but only 60% of PLHIV receiving ART are virally suppressed. The purpose of this study was to understand ART adherence in the Peruvian context, including developing sociodemographic and clinical profiles, evaluating the clinical management strategies, and analyzing the relationships between the variables and adherence of PLHIV managed at a regional HIV clinic in Lambayeque Province (Northern Peru). This was a cross-sectional study with 180 PLHIV adults, non-randomly but consecutively selected with self-reported ART compliance (78.2% of the eligible population). The PLHIV profile (PLHIV-Pro) and the Simplified Medication Adherence Questionnaire (SMAQ) were used to collect sociodemographic information, clinical variables, and data specific to ART adherence. Descriptive analysis of sociodemographic and clinical characteristics was performed. Bivariate analysis was performed with the Mann-Whitney test, Chi square test, and Yates correction. The 180 PLHIV sample included 78.9% men, 49.4% heterosexual, 45% with a detectable HIV-1 viral load less than 40 copies/ml, 58.3% not consistently adherent, and only 26.1% receiving Tenofovir + Lamivudine + Efavirenz. Risk factors significant for non-adherence included concurrent tuberculosis, discomfort with the ART regime, and previous pauses in ART. Multivariate analysis of nested models indicated having children is a protector factor for adherence. Self-reported adherence appeared to be low and the use of first-line therapy is not being prescribed homogeneously. Factors associated with nonadherence are both medical and behavioral, such as having tuberculosis, pausing ART, or experiencing discomfort with ART. The Peruvian government needs to update national technical standards, monitor medication availability, and provide education to health care professionals in alignment with evidence-based guidelines and international recommendations. Instruments to measure adherence need to be developed and evaluated for use in Latin America

EP05.02-003 Durvalumab after Chemoradiotherapy (CRT) in Unresectable Stage III NSCLC. Comparative Study of Two Cohorts in the Real-World Setting

[EN] Introduction: Durvalumab is the new standard of care for unresectable locally advanced NSCLC, with PD-L1 _1% and who did not have progression after CRT treatment in the European Union. Our study compares the effectiveness and the frequency of radiation pneumonitis in patients treated with concurrent CRT with or without durvalumab consolidation during the same period in real clinical practice. Methods: A single-center retrospective study. 71 treated patients with unresectable stage III NSCLC were included between March 2018 and December 2021, 37 with CRT followed by durvalumab and 34 with CRT alone. Real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were calculated since the date of the end CRT. Propensity score matching (PSM) 1:1 was used to account for differences in baseline characteristics. Results: Median age was 67 years (range 46-82). 25.4% of the patients were _75 years old. 78.9% were men and 53.5% former smokers. 54.9% had squamous histology and 28%, 51% and 21% stage IIIA, IIIB and IIIC disease, respectively. The most used scheme was carboplatinpaclitaxel (43.7%), receiving induction chemotherapy in up to 54.9% of patients. 73.2% received between 60-66 Gy doses of radiotherapy. Median time from end of CRT to onset durvalumab was 44 days (range 13-120) with a median of 14 infusions (range 6-27). Of the 34 patients without durvalumab treatment, the expression PD-L1 <1% (58.8%) was the most frequent cause for rejecting consolidation therapy. After PSM analysis, patients distributions were well balanced. With a median follow-up of 19.7 months (range 1.4-36.6); median rw-PFS was 9.3 months (95% CI, 5-13.5) without durvalumab and 17 months (95% CI, 11-22.9) with durvalumab (p¼0.013). Median rw-OS was 19.3 months (95% CI, 3.8-34.8) without durvalumab and 29.9 months (95% CI, 23.3-36.6) with durvalumab (p¼0.241) with a rw-OS% at 6, 18 and 24 months of 90%, 62% and 49% vs 100%, 86% and 74%, respectively. The rate of radiation pneumonitis was more frequent with durvalumab consolidation (56.8% against 44.1%), (p¼0.346), especially within 3 months after CRT. G3 pneumonitis was only observed in the consolidation therapy. Conclusions: Our results demonstrate the effectiveness of durvalumab consolidation after CRT in real-world patients with unresectable stage III NSCLC. Further sample and longer follow-up are required to obtain more accurate results. Active surveillance and appropriate management for radiation pneumonitis are needed, in especially in candidates for consolidation treatmentS

TRANSFORM (Multicenter Experience With Rapid Deployment Edwards INTUITY Valve System for Aortic Valve Replacement) US clinical trial: Performance of a rapid deployment aortic valve

Background: The TRANSFORM (Multicenter Experience With Rapid Deployment Edwards INTUITY Valve System for Aortic Valve Replacement) trial (NCT01700439) evaluated the performance of the INTUITY rapid deployment aortic valve replacement (RDAVR) system in patients with severe aortic stenosis. Methods: TRANSFORM was a prospective, nonrandomized, multicenter (n 1�4 29), single-arm trial. INTUITY is comprised of a cloth-covered balloon- expandable frame attached to a Carpentier-Edwards PERIMOUNT Magna Ease aortic valve. Primary and effectiveness endpoints were evaluated at 1 year. Results: Between 2012 and 2015, 839 patients underwent RDAVR. Mean age was 73.5 8.3 years. Full sternotomy (FS) was used in 59% and minimally invasive surgical incisions in 41%. Technical success rate was 95%. For isolated RDAVR, mean crossclamp and cardiopulmonary bypass times for FS were 49.3 26.9 minutes and 69.2 34.7 minutes, respectively, and for minimally invasive surgical 63.1 25.4 minutes and 84.6 33.5 minutes, respectively. These times were favorable compared with Society of Thoracic Surgeons data- base comparators for FS: 76.3 minutes and 104.2 minutes, respectively, and for minimally invasive surgical, 82.9 minutes and 111.4 minutes, respectively (P<.001). At 30 days, all-cause mortality was 0.8%; valve explant, 0.1%; throm- boembolism, 3.5%; and major bleeding, 1.3%. In patients with isolated aortic valve replacement, the rate of permanent pacemaker implantation was 11.9%. At 1 year, mean effective orifice area was 1.7 cm2; mean gradient, 10.3 mm Hg; and moderate and severe paravalvular leak, 1.2% and 0.4%, respectively

Models and data analysis tools for the Solar Orbiter mission

Context. The Solar Orbiter spacecraft will be equipped with a wide range of remote-sensing (RS) and in situ (IS) instruments to record novel and unprecedented measurements of the solar atmosphere and the inner heliosphere. To take full advantage of these new datasets, tools and techniques must be developed to ease multi-instrument and multi-spacecraft studies. In particular the currently inaccessible low solar corona below two solar radii can only be observed remotely. Furthermore techniques must be used to retrieve coronal plasma properties in time and in three dimensional (3D) space. Solar Orbiter will run complex observation campaigns that provide interesting opportunities to maximise the likelihood of linking IS data to their source region near the Sun. Several RS instruments can be directed to specific targets situated on the solar disk just days before data acquisition. To compare IS and RS, data we must improve our understanding of how heliospheric probes magnetically connect to the solar disk.Aims. The aim of the present paper is to briefly review how the current modelling of the Sun and its atmosphere can support Solar Orbiter science. We describe the results of a community-led effort by European Space Agency's Modelling and Data Analysis Working Group (MADAWG) to develop different models, tools, and techniques deemed necessary to test different theories for the physical processes that may occur in the solar plasma. The focus here is on the large scales and little is described with regards to kinetic processes. To exploit future IS and RS data fully, many techniques have been adapted to model the evolving 3D solar magneto-plasma from the solar interior to the solar wind. A particular focus in the paper is placed on techniques that can estimate how Solar Orbiter will connect magnetically through the complex coronal magnetic fields to various photospheric and coronal features in support of spacecraft operations and future scientific studies.Methods. Recent missions such as STEREO, provided great opportunities for RS, IS, and multi-spacecraft studies. We summarise the achievements and highlight the challenges faced during these investigations, many of which motivated the Solar Orbiter mission. We present the new tools and techniques developed by the MADAWG to support the science operations and the analysis of the data from the many instruments on Solar Orbiter.Results. This article reviews current modelling and tool developments that ease the comparison of model results with RS and IS data made available by current and upcoming missions. It also describes the modelling strategy to support the science operations and subsequent exploitation of Solar Orbiter data in order to maximise the scientific output of the mission.Conclusions. The on-going community effort presented in this paper has provided new models and tools necessary to support mission operations as well as the science exploitation of the Solar Orbiter data. The tools and techniques will no doubt evolve significantly as we refine our procedure and methodology during the first year of operations of this highly promising mission.Peer reviewe