Search

This study investigates a non-orthogonal multiple access (NOMA)-assisted cell-free massive multiple-input multiple-output (MIMO) system, considering the impact of both individual and linear-combination channel estimations. To make the best use of NOMA as an enabler for cell-free massive MIMO systems, user pairing should be employed effectively. Random user pairing naturally leads to a non-optimal solution, whereas an exhaustive search approach is unfavorable for practical systems owing to the high complexity. In this study, we propose an optimal user pairing strategy to group users that jointly optimize the minimum downlink rate per user and power allocation at an acceptable cost of complexity. To address this problem, we first relax the binary variables to continuous variables and then develop an iterative algorithm based on the inner approximation method, yielding at least one locally optimal solution. Numerical results show that the proposed user pairing algorithm outperforms existing counterparts, such as conventional beamforming, random pairing, far pairing, and close-pairing strategies, while it can be performed dynamically, that is, two arbitrary users satisfying the formulated problem can be paired regardless of geographical distance. Finally, our approach demonstrates that the combination channel estimation-based NOMA-assisted cell-free massive MIMO achieves the best result in terms of the downlink rate per user when associated with the proposed algorithm.

Using a rosette-enabled size-based (RESIZE) approach, a desired subset of lymphocytes can be isolated from unwanted lymphocytes of the same size and other cells rapidly and with high purity and yield in a flow-through, passive microfluidic device.

This work investigates the robust beamforming for a multi-antenna internet of things (IoT) system using wireless information and power transmission (WIPT), given that imperfect channel state information (CSI) assumption is accounted.In particular, we investigate the problem of maximizing the worst-case energy harvested, taking into account the quality of service (QoS) constraint of user rate. The proposed problem is naturally a nonconvex problem, which is hard to tackle directly. On one hand, we rely on a classical method, that is semidefinite programming problem (SDP), to handle this by transforming the original nonconvex optimization problem with infinite number of constraints to a relaxed convex one. On the other hand, we propose another algorithm using Symbiotic Organisms Search (SOS) approach that can effciently solve the formulated problem. In the end, numerical results are provided to verify the effectiveness of the SDP-based algorithm in comparison with that of the SOS-based algorithm.

Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).Cross-sectional study.MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.GRS were significantly associated with POAG (Plt; 5 × 10sup-5/sup) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

n this paper, we study the problem of optimizing the weighted total system rate (WSR) for a downlink broadcast communication system using multiple input-multiple output (MIMO) antenna technology, wherein a Base station (BS) transmits multiple data streams simultaneously to K multi-antenna MIMO mobile stations (MSs). Upon the power constraint, the optimal solution is to find the pre-coding matrices at the BS and the decoding matrices at the MSs. However, this type of optimization problem is usually nonlinear and non-convex, so it is relatively difficult to solve by analytical methods. To tackle the problem, we propose a novel algorithm to optimize the WSR of the system based on the Harris Hawking Optimization (HHO) algorithm using the linear least squares mean error (MMSE) filter at the MSs. Numerical results have been used to demonstrate the outperformance of the proposed algorithm, comparing with existing methods such as Block Diagonalism with Waterfilling algorithm and Particle Swarm Optimization, particularly at the low signal-to-noise (SNR) range. In the end, we may propose an adaptive method that combines the advantages of different algorithms at various SNR domains to maximize the system performance.

Aims This study identifies the contribution of leaf matter from individual plant species on water repellency with a focus on the composition of organic compounds and the role of heat in releasing these compounds to soil. Methods Leaf powder from four plant species (Banksia menziesii, Eucalyptus marginata, Allocasuarina fraseriana, Xanthorrhoea preissii) was mixed with acid-washed sand (AWS) under a range of temperatures and WR measured. Plant chemical composition was characterized by extraction of leaf powder and GC/MS analysis. Results Increasing concentrations of plant powder mixed with AWS increased WR for three species; whereas for X. preissii there was no WR at any concentration. Heating increased WR for all species over the range of 30 to 120 °C. B. menziesii had the greatest WR, which was associated with the largest diversity of fatty acids and n-alcohols and highest concentration of alkanes, whereas X. preissii with the smallest WR had only C16 alcohol and C16 fatty acids at relatively low concentration. Conclusions Physically mixing leaf powder with AWS allows the contribution of different plant species on WR to be directly examined. WR appears to be related to differences in the concentrations and diversity of n-alcohols, n-fatty acids, and high n-alkanes in the leaves. The observed temperature effects on WR provide insights into the kinetics of release and dispersal of organic compounds from interstitial material.

In this retrospective cohort study of 94 595 severe acute respiratory syndrome coronavirus 2–positive cases, we developed and validated an algorithm to assess the association between coronavirus disease 2019 (COVID-19) severity and long-term complications (stroke, myocardial infarction, pulmonary embolism/deep vein thrombosis, heart failure, and mortality). COVID-19 severity was associated with a greater risk of experiencing a long-term complication 31–120 days postinfection. Most incident events occurred 31–60 days postinfection and diminished after day 91, except heart failure for severe patients and death for moderate patients, which peaked on days 91–120. Understanding the differential impact of COVID-19 severity on long-term events provides insight into possible intervention modalities and critical prevention strategies.

Background: The lipid hypothesis postulates that lower blood cholesterol is associated with reduced coronary heart disease (CHD) risk, which has been challenged by recent studies that observed a U-shaped relation between cholesterol and mortality. The effect of low cholesterol and CHD risk among Veterans is unclear. Methods: This prospective cohort study included Veterans greater than 18 years of age with baseline outpatient visits from 2002 to 2007 and follow-up to December 30, 2018 in the Veterans Health Administration electronic health record system. Veterans were followed to assess CHD mortality risk in relation to outpatient blood cholesterol levels. We used Cox proportional hazard regression to estimate the hazard ratio (HR) and 95% confidence interval (CI) of CHD mortality associated with total cholesterol (TC). Results: Among 4,467,942 Veterans, 381,871 CHD deaths were recorded. We observed a V-shaped relation between TC and age-, sex, race and smoking-adjusted risk of CHD mortality. The association became U-shaped after adjustment for statin use, body mass index, hypertension, and diabetes. When further adjusted for high-density lipoprotein level, 11 baseline diseases, and applying a 2-year lag analysis, the relation to CHD mortality was J-shaped--flat for TC Conclusions: Based on prospective data for almost 4.5 million adult Veterans, CHD mortality risk steadily increased for TC ≥200mg/dL after adjustment for a range of health conditions. Our results support the lipid hypothesis that lower blood cholesterol is associated with reduced CHD risk and lower prevalence of multimorbidity, mental health disorders, nutritional deficits, and other risk factors for CHD. Furthermore, the hypothesis remained true when TC was low due to use of statins or other lipid-lowering medication. The changes in risk for CHD mortality by TC groups observed in our study (L- to U- to J-shape) highlights the importance of fully adjusting for the presence of multimorbidity and HDL-C to avoid misleading conclusions.

Background: Although recent large randomized clinical trials showed an increased risk of atrial fibrillation (AF) with marine omega-3 fatty acids supplements, it is unclear whether dietary marine omega-3 fatty acids assessed through food frequency questionnaires are associated with AF risk. Hence, we sought to test the hypothesis that dietary eicosapentaenoic acid/docosahexaenoic acid/docosapentaecnoic acid (EPA/DHA/DPA) is associated with a higher risk of AF in a large prospective cohort of US Veterans. Methods: We analyzed data from Million Veteran Program participants who completed self-reported food frequency questionnaires. We used multivariable Cox regression to estimate hazard ratios of AF across quintiles of omega-3 fatty acids consumption and a cubic spline analysis to assess the dose-response relationship between omega-3 fatty acids and AF. Results: Of the 301,294 Veterans studied, the mean intake of omega-3 fatty acids (EPA/DHA/DPA) was 0.39 g/day (SD 0.38), the mean age was 64.9 (SD 12.0) years; 91.2% (274,881 of 301,294) male and 84.0% (253,144 of 301,294) White. Consumption of EPA/DHA/DPA exhibited a non-linear inverse relation with incident AF characterized by an initial decline to 11% at 0.75 g/day of marine omega-3 fatty acids intake followed by a plateau. Conclusions: Contrary to our hypothesis, dietary EPA/DHA/DPA was not associated with a higher risk of AF but was inversely related to AF risk in a non-linear manner.

Breast and gynaecological cancer (BGC) patients receiving chemotherapy may experience high levels of stress during the COVID-19 pandemic. Music interventions may be effective in lowering their stress levels. This study explored stressors, coping strategies, and the feasibility of music interventions among BGC patients in Vietnam. An exploratory qualitative study with individual face-to-face semi-structured interviews was conducted. A convenience sample of BGC patients receiving chemotherapy was recruited from the oncology centre of a public hospital in Vietnam. Twenty patients were interviewed with open-ended questions developed based on the transactional model of stress and coping to explore stress-causing factors and coping strategies and based on guidelines for music therapy practice to explore their music preferences and perceptions. Field notes and interview transcripts were analysed following the qualitative content analysis approach. Two stressor themes were identified: undesirable experiences during treatment and patients’ inability to fulfil their own roles and responsibilities. Our findings revealed a new coping strategy—self-realisation of responsibilities towards the family—that is not listed in the transactional model of stress and coping. Future psychological interventions for stress management among BGC patients should focus on raising the patients’ awareness of their values and responsibilities towards their families. Three categories of preferred music genres for stress reduction were identified: religious, softly melodic, and revolutionary music. The patients were aware of the positive effects of music and had different musical preferences. This study also explored the acceptance of music interventions and facilitators and barriers to implementing them among BGC patients in Vietnam. The findings suggest that before implementing music interventions, the musical preferences, religions, and beliefs of each individual should be considered to achieve desirable results. Music interventions for BGC patients receiving chemotherapy in Vietnam are feasible. Further intervention studies are needed to evaluate their effectiveness.

The study of common heritability, or co-heritability, among multiple traits has been widely established in quantitative and molecular genetics. However, in bacteria, genome-based estimation of heritability has only been considered very recently and no methods are currently available for considering co-heritability. Here we introduce such a method and demonstrate its usefulness by multi-trait analyses of the three major human pathogens \textit{Escherichia coli}, \textit{Neisseria gonorrhoeae} and \textit{Streprococcus pneumoniae}. We anticipate that the increased availability of high-throughput genomic and phenotypic screens of bacterial populations will spawn ample future opportunities to understand the common molecular basis of different traits in bacteria.

In our antioxidant screening of some Vietnamese plant extracts, the CHCl3-soluble fraction from Calotropis gigantea (L.) W.T.Aiton flowers showed moderate DPPH free radical scavenging activity with an IC50 value of 55.8 μg/mL. Thus, a further phytochemical study was carried out to obtain five alkaloids, including a new β-carboline-type alkaloid, caloside H (1). These known compounds were identified as 5-hydroxy-(2-methoxymethyl)pyridine (2), nicotinic acid (3), p-(acetylamino)phenol (4), and thymine (5). These structures were determined based on the NMR spectroscopic analysis. In antioxidant assay, caloside H at concentration of 100 μM showed DPPH radical scavenging capacity with a percentage of inhibition of 40.2%. In addition, a plausible biosynthetic pathway for the formation of caloside H was proposed based on the Schiff base formation and Mannich-like reaction.

In the present study, the photocatalytic activity of Ti-SBA-15/C3N4 catalysts was investigated to degrade 2,4-Dichlorophenoxyacetic acid (2,4-D) herbicides in water under visible light irradiation. The catalysts were synthesized via a simple hydrothermal method and characterized by various analytical techniques, including SAXS, N2 adsorption-desorption isotherms, Zeta potential, PL, FT-IR, XRF, TGA, and UV-DRS. Our study indicated that the 2.5Ti-SBA-15/C3N4 had higher efficiency in the degradation of 2,4-D than Ti-SBA-15 and C3N4. The decomposition of 2,4-D reached 60% under 180 minutes of visible light irradiation at room temperature on 2.5Ti-SBA-15/C3N4. Moreover, the degradation of 2,4-D on Ti-SBA-15/C3N4 was pseudo-first-order kinetics with the highest rate constant (0.00484 min−1), which was much higher than that obtained for other photocatalysts reported recently. Furthermore, the catalyst can be reused at least two times for photodegradation of 2,4-D solution under visible light irradiation within a slight decrease in catalytic activity.

Lead is a heavy metal that produces toxicity in both humans and animals due to oxidative stress. The aim of this study was to synthesize through green channel and evaluate hepatoprotective effect of purslane seeds-selenium nanoparticles (PS-Se NPs) against lead acetate-induced liver toxicity. The PS-Se NPs were made and their particle size and zeta potential were measured. In addition, the IC50 of SP-Se NPs against the HepG-2 liver cancer cell line as well as and LD50 in rats were determined. The PS-Se NPs had a mean particle size of around 54.70 ± 4.55 nm, a negative zeta potential of +17.25 and the observed shape of the nanoparticle was spherical. Also, the IC50 of PS-Se NPs against HepG-2 liver carcinoma cell line is 92.66 μg/mL and the LD50 is 1695 mg/kg b.w. Daily oral administration of PS-Se NPs at concentrations of 33.9 and 84.75 mg/kg b.w. for 30 days to rats treated with lead acetate (0.6 mg/kg b.w.) resulted in significant improvements in ALT, AST, ALP, TNF-α, Bcl-2, P53 and MDA. In contrast, oral administration of PS-Se NPs increased the levels of SOD, GPx and GSH in the liver tissue of lead acetate-treated rats. Furthermore, PS-Se NPs almost normalized these effects in histoarchitecture and ultrasound scanning examination of liver tissue. The PS-Se NPs have protective activity against lead acetate-induced liver tissue injury in rats, according to the biochemical, histological and ultrasound scanning findings.

Aims Frailty is associated with an increased risk of all-cause mortality and cardiovascular (CV) events. Limited data exist from the modern era of CV prevention on the relationship between frailty and CV mortality. We hypothesized that frailty is associated with an increased risk of CV mortality. Methods and results All US Veterans aged ≥65 years who were regular users of Veteran Affairs care from 2002 to 2017 were included. Frailty was defined using a 31-item previously validated frailty index, ranging from 0 to 1. The primary outcome was CV mortality with secondary analyses examining the relationship between frailty and CV events (myocardial infarction, stroke, revascularization). Survival analysis models were adjusted for age, sex, ethnicity, geographic region, smoking, hyperlipidaemia, statin use, and blood pressure medication use. There were 3 068 439 US Veterans included in the analysis. Mean age was 74.1 ± 5.8 years in 2002, 76.0 ± 8.3 years in 2014, 98% male, and 87.5% White. In 2002, the median (interquartile range) frailty score was 0.16 (0.10–0.23). This increased and stabilized to 0.19 (0.10–0.32) for 2006–14. The presence of frailty was associated with an increased risk of CV mortality at every stage of frailty. Frailty was associated with an increased risk of myocardial infarction and stroke, but not revascularization. Conclusion In this population, both the presence and severity of frailty are tightly correlated with CV death, independent of underlying CV disease. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished. Key Question Can an electronic frailty index identify adults aged 65 and older who are at risk of CV mortality and major CV events? Key Finding Among 3 068 439 US Veterans aged 65 and older, frailty was associated with an increased risk of CV mortality at every level of frailty. Frailty was also associated with an increased risk of myocardial infarction and stroke, but not revascularization. Take Home Message Both the presence and severity of frailty are associated with CV mortality and major CV events, independent of underlying CV disease.

Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.

Background Chronic health conditions associated with long-term drug use may pose additional risks to people who use drugs (PWUD) when coupled with COVID-19 infection. Despite this, PWUD, especially those living in rural areas, may be less likely to seek out health services. Previous research has highlighted the increased disease burden of COVID-19 among PWUD. Our manuscript supplements this literature by exploring unique attitudes of PWUD living in rural areas toward the pandemic, COVID-19 vaccination, and the role of harm reduction (HR) organizations in raising health awareness among PWUD. Methods Semi-structured interviews were conducted with 20 PWUD living in rural southern Illinois. Audio recordings were professionally transcribed. A preliminary codebook was created based on interview domains. Two trained coders conducted iterative coding of the transcripts, and new codes were added through line-by-line coding and thematic grouping. Results Twenty participants (45% female, mean age of 38) completed interviews between June and November 2021. Participants reported negative impacts of the pandemic on mental health, financial wellbeing, and drug quality. However, the health impacts of COVID-19 were often described as less concerning than its impacts on these other aspects of life. Many expressed doubt in the severity of COVID-19 infection. Among the 16 unvaccinated participants who reported receiving most of their information from the internet or word of mouth, uncertainty about vaccine contents and distrust of healthcare and government institutions engendered wariness of the vaccination. Distrust of healthcare providers was related to past stigmatization and judgement, but did not extend to the local HR organization, which was unanimously endorsed as a positive institution. Among participants who did not access services directly from the HR organization, secondary distribution of HR supplies by other PWUD was a universally cited form of health maintenance. Participants expressed interest in low-threshold healthcare, including COVID-19 vaccination, should it be offered in the local HR organization’s office and mobile units. Conclusion COVID-19 and related public health measures have affected this community in numerous ways. Integrating healthcare services into harm reduction infrastructures and mobilizing secondary distributors of supplies may promote greater engagement with vaccination programs and other healthcare services. Trial number NCT04427202.

This paper proposes the projected gradient algorithm to find a solution that allows economic restructuring to minimize carbon emission intensity and not hinder targeted economic growth. It develops a general formula to calculate how much each sector should change its share in gross domestic products and its emission intensity such that the economy can have a lower aggregate emission intensity without hindering economic growth. Used data for 30 nations during 1997–2009, the study indicates that if a country follows this proposed optimal restructuring solution, it experiences a lower carbon emission intensity than its initial scenario. This solution is helpful to (1) find the optimal direction and quantitative solutions of a low emission economic structure; (2) continuously check and quantify the differences between the optimal and actual directions of economic structuring for adjusting economic and environmental policies.

Glioblastoma (GBM) tumor cells are found in the perivascular niche microenvironment and are believed to associate closely with the brain microvasculature. However, it is largely unknown how the resident cells of the perivascular niche, such as endothelial cells, pericytes, and astrocytes, influence GBM tumor cell behavior and disease progression. A 3D in vitro model of the brain perivascular niche developed by encapsulating brain-derived endothelial cells, pericytes, and astrocytes in a gelatin hydrogel is described. It is shown that brain perivascular stromal cells, namely pericytes and astrocytes, contribute to vascular architecture and maturation. Cocultures of patient-derived GBM tumor cells with brain microvascular cells are used to identify a role for pericytes and astrocytes in establishing a perivascular niche environment that modulates GBM cell invasion, proliferation, and therapeutic response. Engineered models provide unique insight regarding the spatial patterning of GBM cell phenotypes in response to a multicellular model of the perivascular niche. Critically, it is shown that engineered perivascular models provide an important resource to evaluate mechanisms by which intercellular interactions modulate GBM tumor cell behavior, drug response, and provide a framework to consider patient-specific disease phenotypes.

Summary Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB.

Introduction: A limited number of drugs are available for use in breast cancer patients, and several are not in practical use due to the lack of adequate biomarkers. We have recently demonstrated the feasibility of using machine learning on molecular data from bulk tumor analysis to create a nine-protein signature named VEGF-inhibition Response Predictor (ViRP) for selecting BC patients for treatment with chemotherapy and bevacizumab. The ViRP score is currently being validated in the NAPEER+ clinical trial (EudraCT 2021-005850-27). Increasing evidence suggests that spatial organization of cells within the tumor microenvironment influences survival and response to therapy in numerous cancer types. In methods based on bulk tumor analysis all tumor cells are profiled simultaneously with both colocalized and distant stroma and immune cells. We are thus pursuing information on spatial organization of cellular phenotypes expressing selected cancer related proteins including our nine ViRP proteins. Methods: From the NeoAva (NCT00773695) clinical trial evaluating the effect of bevacizumab in combination with neoadjuvant chemotherapy (n=132 pts), FFPE tissue sections from patients before, during, and after treatment were made. Cyclic immunofluorescence (cyCIF) was used to profile the spatial expression of 32 cancer-signaling and 32 immune-related proteins, comprising our nine ViRP proteins, on FFPE tissue sections from selected patients (n = 20). The Galaxy-ME platform was used for image processing and downstream analysis of spatial protein profiling. Results: Use of cyCIF for spatial analysis enabled for evaluation of malignant cells in the context of surrounding microenvironmental cells, including immune cells. We found that cell type-specific protein abundance and subcellular localization formed a highly heterogenous pattern in the tissue. This was particularly evident for the nine ViRP proteins, and differences in expression between tumor cell populations will be further elucidated. Among the patients selected for cyCIF analysis, 4 were chosen based on misclassification by the ViRP signature. Ongoing studies focus on revealing spatial expression patterns to optimize the ViRP biomarker and explore why misclassification occurs. Furthermore, the observed molecular biology of the evolving tissues under treatment in responding and non-responding patients may reveal new biomarkers indicative of treatment response or resistance. Conclusion: We observe that the expression of proteins in tumor tissues is highly heterogeneous, and thus include numerous features not captured by bulk tumor analysis. Future development of new predictive tools and biomarkers that integrate molecular data which is multiparametric and spatial will set the stage for a new class of biomarkers in cancer diagnostics. Citation Format: Mads Haugland Haugen, David Kilburn, Hongli Ma, Cameron Watson, Allison Creason, Dong Zhang, Maria Aa Dahle, Ole Christian Lingjaerde, Marianne L. Smebye, Oeystein Garred, Mette S. Foersund, Mai T. Nguyen, Gunhild M. Maelandsmo, Gordon Mills, Olav Engebraaten. Spatial protein profiling by cyclic immunofluorescence to interpret and improve bulk tumor-based predictor of response to chemotherapy with bevacizumab in neoadjuvant breast cancer treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5627.

The present study aimed to distinguish light on the protective of Moringa oleifera seeds dried ethanolic extract on the toxicity in liver and kidney induced by acetamprid pesticide which widely produced and used for agricultural treatment in Egypt. Physico-chemical parameters and identification of fatty acid composition of Moringa oleifera seeds oil were elvaluated. In addition , the biological effects of bioactive components of seeds dried extract at concentration 200 mg/kg b.w. oil as additives into the diets on kidney and liver functions , lipid profile ,serum glucose levels , hematological parameters and histopatholgical examination of experimental rats were evaluated. From the obtained results , it could be noticed that the total phenolic acid , flavonoids and tannin contents in Moringa oleifera seeds of the dried ethanolic extract were 44.25±1.13 , 114.36±0.72 and 20.77±1.10 ug/g , respectively. Total antioxidant capacity of dried ethanolic extract of Moringa oleifera seeds was found to be 143.29±0.37 , 178.10±2.18 , 189.18±2.06 and 222.47±0.81 at 50 , 100 , 150 and 200 ug/ml . Also, the results showed that the Moringa oleifera (MO) seeds oil extract was dominated by the high percentage of total unsaturated fatty acid (80.29%) than its saturated (19.71%). On the other hand , the results showed that there were significant increasment of biochemical parameters such as serum urea and creatinine (as function of kidney) , as well as ALT and AST activity also albumin and total protein (as function of liver) , total cholesterol , triglyceride and serum glucose levels of the experimental rats. These values were found significantly decreased in all treatments rats fed diets containing MO seeds oils extract at dose of 200 mg /ml b.w. as compared with the group treated by acetampride (toxicated group).The results of the effects of MO seeds extract on hematological parameters of intoxicated rats caused significant decreasments in total white blood cells counts (WBCs) . While, MCV , MCH and MCHC were significantly unchanged relative to those of different from the control group but haemglobin (Hb) and red blood cells (RBCs) was increased. Histopathological studies confirmed chemical analysis results. Finally, from the obtained results and histopathological examination , it could be concluded that the administration of MO seeds dried extract of ethanolic oils might improve the liver and kidney functions in the present experimental rats.

OBJECTIVE To evaluate feline injection site-associated sarcoma (FISAS) and oral squamous cell carcinoma (FOSCC) cells in 3-D hydrogel-based cell cultures to determine chemosensitivity to carboplatin at concentrations comparable to those eluted from carboplatin-impregnated calcium sulfate hemihydrate (C-ICSH) beads. SAMPLE 2 immortalized cell lines, each from a histologically confirmed primary FISAS and FOSCC. PROCEDURES Hydrogels (10% wt/vol) were formed via UV exposure from methacrylamide-functionalized gelatin dissolved in PBSS. For each cell line, approximately 100,000 cells were encapsulated per hydrogel. Three cell-seeded 3-D hydrogels were evaluated for each carboplatin concentration (0, 150, 300, 450, and 600 µM) across 3 experiments. Drug efficacy was assessed by luminescence assay 72 hours after treatment. Growth of tumor cells treated with 300 µM or 600 µM carboplatin was evaluated using live-cell morphology imaging and confocal microscopy at 3, 7, and 14 days after treatment. RESULTS Mean half-maximal inhibitory concentration (IC50) values for FISAS and FOSCC cells ranged from 123 to 171 µM and 155 to 190 µM, respectively, based on luminescence assay. Viability at 3, 7, and 14 days for both cell lines at 300 µM carboplatin was 50%, 25%, and 5% and at 600 µM carboplatin was 25%, 10%, and < 5%. CLINICAL RELEVANCE 3-D hydrogel cell culture systems supported growth of feline tumor cells for determination of in vitro chemosensitivity. IC50s of each cell line were within the range of carboplatin concentrations eluted from C-ICSH beads. Cells from FISAS and FOSCC cell lines treated with carboplatin showed dose-dependent and time-dependent decreases in viability.

Biomaterials that replicate patterns of microenvironmental signals from the stem cell niche offer the potential to refine platforms to regulate stem cell behavior. While significant emphasis has been placed on understanding the effects of biophysical and biochemical cues on stem cell fate, vascular-derived or angiocrine cues offer an important alternative signaling axis for biomaterial-based stem cell platforms. Elucidating dose-dependent relationships between angiocrine cues and stem cell fate are largely intractable in animal models and 2D cell cultures. In this study, microfluidic mixing devices are leveraged to generate 3D hydrogels containing lateral gradients in vascular density alongside murine hematopoietic stem cells (HSCs). Regional differences in vascular density can be generated via embossed gradients in cell, matrix, or growth factor density. HSCs co-cultured alongside vascular gradients reveal spatial patterns of HSC phenotype in response to angiocrine signals. Notably, decreased Akt signaling in high vessel density regions led to increased expansion of lineage-positive hematopoietic cells. This approach offers a combinatorial tool to rapidly screen a continuum of microenvironments with varying vascular, biophysical, and biochemical cues to reveal the influence of local angiocrine signals on HSC fate.

Glioblastoma (GBM) tumor cells are found in the perivascular niche microenvironment and are believed to associate closely with the brain microvasculature. However, it is largely unknown how the resident cells of the perivascular niche, such as endothelial cells, pericytes, and astrocytes, influence GBM tumor cell behavior and disease progression. We describe a three-dimensional in vitro model of the brain perivascular niche developed by encapsulating brain-derived endothelial cells, pericytes, and astrocytes in a gelatin hydrogel. We show that pericytes and astrocytes explicitly contribute to vascular architecture and maturation. We use co-cultures of patient-derived GBM tumor cells with brain microvascular cells to identify a role for pericytes and astrocytes in establishing a perivascular niche environment that modulates GBM cell invasion, proliferation, and therapeutic response. Engineered models provides unique insight regarding the spatial patterning of GBM cell phenotypes in response to a multicellular model of the perivascular niche. Critically, we show that engineered perivascular models provide an important resource to evaluate mechanisms by which inter- cellular interactions modulate GBM tumor cell behavior, drug response, and provide a framework to consider patient-specific disease phenotypes.

Background Drug overdose rates in the United States have been steadily increasing, particularly in rural areas. The COVID-19 pandemic and associated mitigation strategies may have increased overdose risk for people who use drugs by impacting social, community, and structural factors. Methods The study included a quantitative survey focused on COVID-19 administered to 50 people who use drugs and semi-structured qualitative interviews with 17 people who use drugs, 12 of whom also participated in the quantitative survey. Descriptive statistics were run for the quantitative data. Qualitative coding was line-by-line then grouped thematically. Quantitative and qualitative data were integrated during analysis. Results Findings demonstrate how COVID-19 disruptions at the structural and community level affected outcomes related to mental health and drug use at the individual level. Themes that emerged from the qualitative interviews were (1) lack of employment opportunities, (2) food and housing insecurity, (3) community stigma impacting health service use, (4) mental health strains, and (5) drug market disruptions. Structural and community changes increased anxiety, depression, and loneliness on the individual level, as well as changes in drug use patterns, all of which are likely to increase overdose risk. Conclusion The COVID-19 pandemic, and mitigation strategies aimed at curbing infection, disrupted communities and lives of people who use drugs. These disruptions altered individual drug use and mental health outcomes, which could increase risk for overdose. We recommend addressing structural and community factors, including developing multi-level interventions, to combat overdose. Trial registration Clinicaltrails.gov: NCT04427202. Registered June 11, 2020: https://clinicaltrials.gov/ct2/show/NCT04427202?term=pho+mai&draw=2&rank=3

Purpose Opioid overdose education and naloxone distribution (OEND) for use by laypersons has been shown to be safe and effective, but implementation in the emergency department (ED) setting is challenging. Recent literature has shown a discouragingly low rate of obtainment of naloxone that is prescribed in the ED setting. We conducted a study to evaluate the feasibility of point-of-care (POC) distribution of naloxone in an ED, hypothesizing a rate of obtainment higher than prescription fill rates reported in previous studies. Summary A multidisciplinary team of experts, including pharmacists, physicians, nurses, and case management professionals used an iterative process to develop a protocol for POC OEND in the ED. The protocol includes 5 steps: (1) patient screening, (2) order placement in the electronic health record (EHR), (3) a patient training video, (4) dispensing of naloxone kit, and (5) written discharge instructions. The naloxone kits were assembled, labeled to meet requirements for a prescription, and stored in an automated dispensing cabinet. Two pharmacists, 30 attending physicians, 65 resident physicians, and 108 nurses were trained. In 8 months, 134 orders for take-home naloxone were entered and 117 naloxone kits were dispensed, resulting in an obtainment rate of 87.3%. The indication for take-home naloxone kit was heroin use for 61 patients (92.4%). Conclusion POC naloxone distribution is feasible and yielded a rate of obtainment significantly higher than previous studies in which naloxone was prescribed. POC distribution can be replicated at other hospitals with low rates of obtainment.

Background: Overdose is a leading cause of morbidity and mortality among people who inject drugs. Illicitly manufactured fentanyl is now a major driver of opioid overdose deaths. Methods: Semi-structured interviews were conducted with 23 participants (19 persons who inject drugs and 4 service providers) from rural southern Illinois. Data were analyzed using constant comparison and theoretical sampling methods. Results: Participants were concerned about the growing presence of fentanyl in both opioids and stimulants, and many disclosed overdose experiences. Strategies participants reported using to lower overdose risk included purchasing drugs from trusted sellers and modifying drug use practices by partially injecting and/or changing the route of transmission. Approximately half of persons who inject drugs sampled had heard of fentanyl test strips, however fentanyl test strip use was low. To reverse overdoses, participants reported using cold water baths. Use of naloxone to reverse overdose was low. Barriers to naloxone access and use included fear of arrest and opioid withdrawal. Conclusions: People who inject drugs understood fentanyl to be a potential contaminant in their drug supply and actively engaged in harm reduction techniques to try to prevent overdose. Interventions to increase harm reduction education and information about and access to fentanyl test strips and naloxone would be beneficial.

Background Ginger rhizome (Zingiber officinale) is a well-known spice and medicinal plant that is widely used in the Egyptian market as a spice, flavor and medicinal herb for different diseases. Since it is not cultivated as rhizomes in Egypt, ginger is imported from other countries, which may impact its quality. In this study, UV spectroscopy and high-performance liquid chromatography (HPLC) were applied as efficient available techniques for the discrimination and quality control of ginger collected from different geographical origins in combination with chemometrics. In addition, HPLC was applied to investigate the stability of ginger samples upon storage for 3 years to trace the changes in their main active constituents. Results Data obtained from both UV and HPLC in combination with Principal Component Analysis (PCA) displayed proper discrimination of the samples according to their geographical origins. Regarding the stability study, ginger samples showed a significant decrease in quality after storage for 3 years, in which significant variation in the main pungent principles (6-, 8-, 10-gingerols and 6-shogaol) were observed. PCA failed to discriminate between ginger samples after long-time storage, so the applied model could discriminate between ginger samples before and after storage. Conclusion UV and HPLC in combination with chemometrics can be applied as a successful tool for the study of quality, stability and geographical discrimination of ginger. © 2020 Society of Chemical Industry.

Significance Axonal injury plays a major role in many neurodegenerative diseases. The dual leucine zipper kinase (DLK) signaling pathway is a key regulator of axonal injury-induced neuronal cell death; however, DLK also has an important role in promoting axonal outgrowth. Therefore, inhibiting DLK as a therapeutic approach for neurodegenerative diseases is limited to a neuroprotective outcome without axon regeneration, prohibiting restoration of function. In fact, there are currently no strategies that provide long-term neuroprotection and axonal regeneration after injury. Here, we identified the germinal cell kinase four (GCK-IV) family of kinases as targets to maximize neuroprotection while promoting axon regeneration, making it an attractive therapeutic approach for a subset of neurodegenerative diseases., Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as a key mediator of this process. However, while DLK inhibition is robustly protective in a wide range of neurodegenerative disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that are known to both improve long-term survival and promote regeneration. To identify such a neuroprotective target, we conducted a set of complementary high-throughput screens using a protein kinase inhibitor library in human stem cell-derived retinal ganglion cells (hRGCs). Overlapping compounds that promoted both neuroprotection and neurite outgrowth were bioinformatically deconvoluted to identify specific kinases that regulated neuronal death and axon regeneration. This work identified the role of germinal cell kinase four (GCK-IV) kinases in cell death and additionally revealed their unexpected activity in suppressing axon regeneration. Using an adeno-associated virus (AAV) approach, coupled with genome editing, we validated that GCK-IV kinase knockout improves neuronal survival, comparable to that of DLK knockout, while simultaneously promoting axon regeneration. Finally, we also found that GCK-IV kinase inhibition also prevented the attrition of RGCs in developing retinal organoid cultures without compromising axon outgrowth, addressing a major issue in the field of stem cell-derived retinas. Together, these results demonstrate a role for the GCK-IV kinases in dissociating the cell death and axonal outgrowth in neurons and their druggability provides for therapeutic options for neurodegenerative diseases.

Introduction: Today, ceramic plays a vital role in restorative dentistry. Common uses include full-coverage crown, inlays, onlays, and ceramic bridges. The demands for esthetics in dental restoration continue, new technologies tend to improve the material properties and develop new methods for application. Objective: This study aimed to evaluate the effect of different solutions on two milled esthetic restorative materials. Material and methods: In this study, a total of thirty blocks samples were machine milled by the aid of computer-aided design & computer-aided manufacturing (CAD/CAM) system. The samples were divided according to the material of construction into two main groups. Each group was composed of 15 samples as follows: Group I: constructed from milled composite resin blocks. Group II: constructed from milled feldspathic porcelain blocks. All sample groups were then immersed in 20ml of artificial saliva for 24 hours to be a baseline assessment. Results: Spectrophotometer measurements of all the groups and subgroups revealed statically significant higher mean ΔE values for ceramic groups than the composite resin groups. All changes in the colour were clinically acceptable except for ceramic samples immersed in acid media. Conclusion: By reducing the pH value, increasing the acidity of the immersion media that led to an increase in the surface roughness of the tested restorative materials (composite resin and ceramic).

Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

SummaryBackgroundNanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. In a Phase 1 and 2 studies, (NCT04683484) the vaccine was found to be safe and induce a robust immune response in healthy adult participants.MethodsWe conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, immunogenicity, and protective efficacy of the Nanocovax vaccine against Covid-19 in approximately 13,007 volunteers aged 18 years and over. The immunogenicity was assessed based on Anti-S IgG antibody response, surrogate virus neutralization, wild-type SARS-CoV-2 neutralization and the types of helper T-cell response by intracellular staining (ICS) for interferon gamma (IFNg) and interleukin-4 (IL-4). The vaccine efficacy (VE) was calculated basing on serologically confirmed cases of Covid-19.FindingsUp to day 180, incidences of solicited and unsolicited adverse events (AE) were similar between vaccine and placebo groups. 100 serious adverse events (SAE) were observed in both vaccine and placebo groups (out of total 13007 participants). 96 out of these 100 SAEs were determined to be unrelated to the investigational products. 4 SAEs were possibly related, as determined by the Data and Safety Monitoring Board (DSMB) and investigators. Reactogenicity was absent or mild in the majority of participants and of short duration. These findings highlight the excellent safety profile of Nanocovax.Regarding immunogenicity, Nanocovax induced robust IgG and neutralizing antibody responses. Importantly, Anti S-IgG levels and neutralizing antibody titers on day 42 were higher than those of natural infected cases. Nanocovax was found to induce Th2 polarization rather than Th1.Post-hoc analysis showed that the VE against symptomatic disease was 51.5% (95% confidence interval [CI] was [34.4%-64.1%]. VE against severe illness and death were 93.3% [62.2-98.1]. Notably, the dominant strain during the period of this study was Delta variant.InterpretationNanocovax 25 microgram (mcg) was found to be safe with the efficacy against symptomatic infection of Delta variant of 51.5%.FundingResearch was funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04922788.

Objective:To examine the association between adherence to plant-based diets and mortality.Design:Prospective study. We calculated a plant-based diet index (PDI) by assigning positive scores to plant foods and reverse scores to animal foods. We also created a healthful PDI (hPDI) and an unhealthful PDI (uPDI) by further separating the healthy plant foods from less-healthy plant foods.Setting:The VA Million Veteran Program.Participants:315 919 men and women aged 19–104 years who completed a FFQ at the baseline.Results:We documented 31 136 deaths during the follow-up. A higher PDI was significantly associated with lower total mortality (hazard ratio (HR) comparing extreme deciles = 0·75, 95 % CI: 0·71, 0·79, Ptrend < 0·001]. We observed an inverse association between hPDI and total mortality (HR comparing extreme deciles = 0·64, 95 % CI: 0·61, 0·68, Ptrend < 0·001), whereas uPDI was positively associated with total mortality (HR comparing extreme deciles = 1·41, 95 % CI: 1·33, 1·49, Ptrend < 0·001). Similar significant associations of PDI, hPDI and uPDI were also observed for CVD and cancer mortality. The associations between the PDI and total mortality were consistent among African and European American participants, and participants free from CVD and cancer and those who were diagnosed with major chronic disease at baseline.Conclusions:A greater adherence to a plant-based diet was associated with substantially lower total mortality in this large population of veterans. These findings support recommending plant-rich dietary patterns for the prevention of major chronic diseases.