Load Levels Research Articles

Creep Failure Characteristics and Mathematical Modeling of High-Density Polyethylene Geomembranes under High Stress Levels

To explore the creep characteristics of geomembrane under different tensile stresses, a series of creep tests were carried out on high-density polyethylene (HDPE) geomembrane specimens. For the interpretation and fitting of the experimental data, refined approximation functions were proposed. Particular attention was paid to the creep failure behavior under high tensile stresses, i.e., 70%, 80%, and 90% of maximum peak stress. To investigate the effects of size on the mechanical response, experiments with two different membrane thicknesses were conducted. The results obtained under high stress levels were compared with creep tests at medium and low stress levels. Depending on load level, different creep characteristics can be distinguished. In the secondary creep state, the creep velocity is higher for higher load levels. In contrast to the medium and low load levels, the geomembrane under high stresses underwent the tertiary creep stage after instantaneous deformation and primary and secondary creep stages. In some tests, it was observed that under very high stress levels, creep velocity does not necessarily follow the expected trend and creep rupture can occur within a short time. For numerical simulation, an improved mathematical model was proposed to reproduce in a unified manner the experimental data of the whole non-linear evolution of creep elongation under different stress levels.

Exploring the effect of cognitive load in scenarios of daily driving

AbstractAlthough driving to and from work is an unavoidable part of the working life of many people, little is known about the relationship between work-related and drive-related cognitive load in daily commuting. To explore those relationships, Study 1 examined the effect of a demanding driving period on the performance of a subsequent cognitive task (mimicking a home-to-work commuting scenario). That driving-related higher cognitive load than the control condition was associated with an increased accuracy in the following cognitive task. Study 2 examined the effects of a period of demanding cognitive tasks on the performance of a subsequent driving task (mimicking a work-to-home commuting scenario). Although no reliable effect on speed or lane keeping ability in a virtual motorway scenario was observed, the completion of tasks under the higher cognitive load condition before driving led to a modest increase in the distance kept from the car ahead. The two sets of findings suggest that moderate levels of cognitive load could modulate the performance in timely contiguous tasks. The process underpinning possible spillover effects with such timestamp is unknow but might be linked to the activation of long-lasting attentional processes involving alertness. Hence, this exploratory study can be a catalyst for future studies investigating the interplay between cognitive load and driving in scenarios of daily commuting.

Self-Reporting Conjugated Polymer Nanoparticles for Superoxide Generation and Detection.

Conjugated polymer nanoparticles (CPNs or Pdots) have become increasingly popular fluorophores for multimodal applications that combine imaging with phototherapeutic effects. Reports of CPNs in photodynamic therapy applications typically focus on their ability to generate singlet oxygen. Alternatively, CPN excited states can interact with oxygen to form superoxide radical anion and a CPN-based hole polaron, both of which can have deleterious effects on fluorescence properties. Here, we demonstrate that CPNs prepared from the common conjugated polymer poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(1,4-benzo-{2,1',3}-thiadiazole)] (PFBT, also known as F8BT) generate superoxide upon irradiation. We use the same CPNs to detect superoxide by doping them with a superoxide-responsive hydrocyanine dye developed by Murthy and co-workers. Superoxide induces off-to-on fluorescence switching by converting quenching hydrocyanine dyes to fluorescent cyanine dyes that act as fluorescence resonance energy transfer (FRET) acceptors for PFBT chromophores. Amplified FRET from the multichromophoric CPNs yields fluorescence signal intensities that are nearly 50 times greater than when the dye is excited directly or over 100 times greater when signal readout is from the CPN channel. The dye loading level governs the maximum amount of superoxide that induces a change in fluorescence properties and also influences the rate of superoxide generation by furnishing competitive excited state deactivation pathways. These results suggest that CPNs can be used to deliver superoxide in applications in which it is desirable and provide a caution for fluorescence-based CPN applications in which superoxide can damage fluorophores.

Hygienic quality of food from animal origin and antibiotic resistance of Escherichia coli in a border region of Algeria

Food of animal origin such as milk and meat have a high nutritional value and form an important part of the human and animal diet, but are difficult to produce and are highly perishable. Additionally significant socio–economic loss will result if production and/or storage conditions are neglected, whether through loss of the food or illnesses caused by consumption and treatment. It was in this context that we carried out this study, to assess the hygienic quality of cow’s milk and meat produced and consumed in a border region of Algeria. A total of 130 samples were taken from animal foodstuffs (raw cow’s milk, sheep carcasses, chicken and turkey meat) at farm, abattoir and butchery levels. Mesophilic aerobic flora, total coliforms, thermotolerant coliforms and Escherichia coli were enumerated, and the sensitivity of the E. coli to certain antibiotics most commonly used in human and veterinary medicine was assessed. High levels of contamination and bacterial loads ranging from 5.36×102 CFU·mL–1 for milk, to 1.56×105 CFU·cm–2 for sheep meat, some of this foodstuffs are acceptable but represent a food hazard, and others are not acceptable according to regulations. A high percentage of multiresistant strains and worrying resistance rates were detected, and if the necessary measures are not taken as a matter of urgency in the context of “One Health”, the situation is likely to worsen and human and animal health will be affected.

Dissociable functional responses along the posterior-anterior gradient of the frontal and parietal cortices revealed by parametric working memory and training.

While the storage capacity is limited, accumulating studies have indicated that working memory (WM) can be improved by cognitive training. However, understanding how exactly the brain copes with limited WM capacity and how cognitive training optimizes the brain remains inconclusive. Given the hierarchical functional organization of WM, we hypothesized that the activation profiles along the posterior-anterior gradient of the frontal and parietal cortices characterize WM load and training effects. To test this hypothesis, we recruited 51 healthy volunteers and adopted a parametric WM paradigm and training method. In contrast to exclusively strengthening the activation of posterior areas, a broader range of activation concurrently occurred in the anterior areas to cope with increased memory load for all subjects at baseline. Moreover, there was an imbalance in the responses of the posterior and anterior areas to the same increment of 1 item at different load levels. Although a general decrease in activation after adaptive training, the changes in the posterior and anterior areas were distinct at different memory loads. Particularly, we found that the activation gradient between the posterior and anterior areas was significantly increased at load 4-back after adaptive training, and the changes were correlated with improvement in WM performance. Together, our results demonstrate a shift in the predominant role of posterior and anterior areas in the frontal and parietal cortices when approaching WM capacity limits. Additionally, the training-induced performance improvement likely benefits from the elevated neural efficiency reflected in the increased activation gradient between the posterior and anterior areas.

Characterization of Acoustic Emissions from Concrete Based on Energy Activity Coefficient

Single-stage compression loading experiments were carried out on concrete specimens of various strengths to explore the characteristic parameters of the acoustic emission signal and its damage evolution law in the concrete damage process. These specimens were monitored in real time with acoustic emission and DIC instruments during the loading process, and internal pores and slices were scanned with CT scanning instruments after compression. The acoustic emission phenomenon was expressed using the energy activity coefficient, and the law relating to the phenomenon was summarized. The results show that when the peak and mean values in the first adjacent time domain grow rapidly, the specimen produces a large crack and enters the stage of rapid crack development, which can be taken as an indication of the impending damage to the specimen. The energy activity coefficient reflects the damage development intensity as follows: the smaller the energy activity coefficient, the more the cracks developed; the faster the speed, the larger the deformation. With an increase in the load level, the energy activity coefficient gradually tends to stabilize, and the specimen enters the stage of rapid crack development. However, when the energy activity coefficient suddenly increases again, the specimen is destabilized and destroyed. Therefore, the energy activity coefficient responds to the degree of congenital defects in the specimen. As the load increases, the energy activity coefficient is more stable, and the defects are smaller; in contrast, the energy activity coefficient drastically oscillating indicates that the material is very defective.

Investigation and numerical simulation study on the vertical bearing mechanism of large-diameter overlength piles in water-enriched soft soil areas

Abstract With the development of urbanization, there is an increasing demand for higher land utilization rates, leading to the emergence of high-rise residential and commercial complexes. Additionally, in coastal areas, the presence of soft soil and low bearing capacity of the foundation necessitate higher foundation bearing capacity. Large-diameter, super-long piles have been widely employed in engineering projects to address these challenges effectively. This study analyzes their vertical bearing characteristics through field load tests and determines vertical load distribution and transfer mechanisms by using Brillouin Optical Time Domain Reflectometry. A numerical computation and analysis method based on PLAXIS 3D was established, examining the effects of parameters such as pile diameter, length, and soil modulus on the vertical bearing characteristics. Results indicate that large-diameter, super-long piles mainly bear loads through side friction, with the tip bearing less load. As load levels increase, axial force increases linearly above 40 m depth and becomes nonlinear below. Frictional resistance is significant below 40 m at 3,700 kN load. Parameter analysis shows that increasing pile length and diameter enhances bearing capacity, suggesting this method to improve pile foundation capacity in engineering.

Enhancing mechanical properties of GFRP–aluminum joints through Z pinning: a low velocity shear impact study

Studying the mechanical responses of GFRP and aluminum samples under varying loads is crucial for developing methods to enhance their mechanical properties. This research investigates the impact of z-pinning on single-lap adhesive joints through low-velocity shear impact tests. The study involves testing two types of joints: single-lap adhesive joints and single-lap hybrid pin-adhesive joints with six reinforcing pins, subjected to drop weight tests at load levels of 22.5, 27.5, and 32.4 J. The findings demonstrate that z-pinning can increase the joints’ load-bearing capacity by up to 18.87% and energy absorption by 20.58%. This enhancement is attributed to the additional composite substrate layers in the hybrid joint, which help absorb impact loads. In contrast, in the single-lap adhesive joint, only the layer adjacent to the adhesive bears the impact load. Observations from the tests indicate that in the single-lap adhesive joint, the first composite layer next to the adhesive undergoes complete delamination, whereas in the hybrid joint, all laminates fracture at the steel pins. In summary, this study underscores the significant potential of z-pinning to improve single-lap adhesive joints, providing an innovative approach to enhance their load-bearing capacity and energy absorption.

Enhancing mechanical properties of GFRP–aluminum joints through Z pinning: a low velocity shear impact study

Studying the mechanical responses of GFRP and aluminum samples under varying loads is crucial for developing methods to enhance their mechanical properties. This research investigates the impact of z-pinning on single-lap adhesive joints through low-velocity shear impact tests. The study involves testing two types of joints: single-lap adhesive joints and single-lap hybrid pin-adhesive joints with six reinforcing pins, subjected to drop weight tests at load levels of 22.5, 27.5, and 32.4 J. The findings demonstrate that z-pinning can increase the joints’ load-bearing capacity by up to 18.87% and energy absorption by 20.58%. This enhancement is attributed to the additional composite substrate layers in the hybrid joint, which help absorb impact loads. In contrast, in the single-lap adhesive joint, only the layer adjacent to the adhesive bears the impact load. Observations from the tests indicate that in the single-lap adhesive joint, the first composite layer next to the adhesive undergoes complete delamination, whereas in the hybrid joint, all laminates fracture at the steel pins. In summary, this study underscores the significant potential of z-pinning to improve single-lap adhesive joints, providing an innovative approach to enhance their load-bearing capacity and energy absorption.

Investigation and numerical simulation study on the vertical bearing mechanism of large-diameter overlength piles in water-enriched soft soil areas

Abstract With the development of urbanization, there is an increasing demand for higher land utilization rates, leading to the emergence of high-rise residential and commercial complexes. Additionally, in coastal areas, the presence of soft soil and low bearing capacity of the foundation necessitate higher foundation bearing capacity. Large-diameter, super-long piles have been widely employed in engineering projects to address these challenges effectively. This study analyzes their vertical bearing characteristics through field load tests and determines vertical load distribution and transfer mechanisms by using Brillouin Optical Time Domain Reflectometry. A numerical computation and analysis method based on PLAXIS 3D was established, examining the effects of parameters such as pile diameter, length, and soil modulus on the vertical bearing characteristics. Results indicate that large-diameter, super-long piles mainly bear loads through side friction, with the tip bearing less load. As load levels increase, axial force increases linearly above 40 m depth and becomes nonlinear below. Frictional resistance is significant below 40 m at 3,700 kN load. Parameter analysis shows that increasing pile length and diameter enhances bearing capacity, suggesting this method to improve pile foundation capacity in engineering.

Effectiveness of desertliving cistanche in managing hyperlipidemic osteoporosis in ovariectomized rats through the PI3K/AKT signaling pathway

BackgroundTo aim of this study is to assess the mechanism through which Desertliving Cistanche modulates the PI3K/AKT signaling pathway in the treatment of hyperlipidemic osteoporosis in ovariectomized rats.MethodsWe randomly assigned specific-pathogen-free (SPF) rats into five groups (n = 10 per group). The normal control group received a standard diet, while the model group, atorvastatin group, diethylstilbestrol group, and treatment group were fed a high-fat diet. Four weeks later, bilateral ovariectomies were conducted, followed by drug interventions. After six weeks of treatment, relevant indicators were compared and analyzed.ResultsCompared to the normal control group, rats in the model group exhibited blurred trabecular morphology, disorganized osteocytes, significantly elevated levels of bone-specific alkaline phosphatase (BALP), bone Gla-protein (BGP), total cholesterol (TC), tumor necrosis factor-α (TNF-α), and receptor activator of NF-κB ligand (RANKL). Also, the model group revealed significantly reduced levels of ultimate load, fracture load, estradiol (E2), bone mineral density (BMD), osteoprotegerin (OPG), and phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) in femoral tissue. The atorvastatin group presented with higher TC and TNF-α levels compared to the normal control group. Conversely, the treatment group demonstrated enhanced trabecular morphology, denser structure, smaller bone marrow cavities, and reduced BALP, BGP, TC, TNF-α, and RANKL levels. Furthermore, the treatment group exhibited higher levels of E2, BMD, OPG, and PI3K and Akt in bone tissue compared to the model group. The treatment group also had lower TC and TNF-α levels than the atorvastatin group. Biomechanical analysis indicated that after administration of Desertliving Cistanche, the treatment group had reduced body mass, increased ultimate and fracture load of the femur, denser bone structure, smaller bone marrow cavities, and altered periosteal arrangement compared to the model group.ConclusionOur study revealed that Desertliving Cistanche demonstrated significant efficacy in preventing and treating postmenopausal hyperlipidemic osteoporosis in rats.

Deciphering the cis- regulatory landscape of natural yeast Transcript Leaders.

Protein synthesis is a vital process that is highly regulated at the initiation step of translation. Eukaryotic 5' transcript leaders (TLs) contain a variety of cis -regulatory features that influence translation and mRNA stability. However, the relative influences of these features in natural TLs are poorly characterized. To address this, we used massively parallel reporter assays (MPRAs) to quantify RNA levels, ribosome loading, and protein levels from 11,027 natural yeast TLs in vivo and systematically compared the relative impacts of their sequence features on gene expression. We found that yeast TLs influence gene expression over two orders of magnitude. While a leaky scanning model using Kozak contexts and uAUGs explained half of the variance in expression across transcript leaders, the addition of other features explained ∼70% of gene expression variation. Our analyses detected key cis -acting sequence features, quantified their effects in vivo, and compared their roles to motifs reported from an in vitro study of ribosome recruitment. In addition, our work quantitated the effects of alternative transcription start site usage on gene expression in yeast. Thus, our study provides new quantitative insights into the roles of TL cis-acting sequences in regulating gene expression.

Effects of divided attention on movement-related cortical potential in community-dwelling elderly adults: a preliminary study

Dual-tasking is defined as performing two or more tasks concurrently. This study aimed to investigate the effect of divided attention on movement-related cortical potential (MRCP) during dual-task performance in 11 community-dwelling elderly individuals while the load of the secondary task was altered. MRCP was recorded during a single task (ST), simple dual task (S-DT), and complex dual task (C-DT) as no-, low-, and high-load divided attention tasks, respectively. The ST involved self-paced tapping with an extended right index finger. In the S-DT and C-DT, the subjects simultaneously performed the ST and a visual number counting task with different levels of load. The coefficient of variation of movement frequency was significantly more variable in the C-DT than in the ST. The MRCP amplitude from electroencephalography electrode C3, contralateral to the moving hand, was significantly higher in the C-DT than in the ST. Higher attention diversion led to a significant reduction in MRCP amplitude in the participants. These results suggest that attention division in dual-task situations plays an important role in movement preparation and execution. We propose that MRCP can serve as a marker for screening the ability of older individuals to perform dual-tasks.

Fatigue performance simulation of reinforced concrete beams externally strengthened with side bonded CFRP sheets

Damaged Reinforced Concrete (RC) beams are commonly strengthened by bonding Carbon Fiber Reinforced Polymer (CFRP) strips to their soffits. However, inaccessible or narrow soffits limit the use of bottom-bonded CFRP strips. The Side Bonded (SB) CFRP technique overcomes this, yet studies on SB-CFRP-reinforced beams' fatigue behavior are limited. This paper presents a Finite Element (FE) model for simulating the fatigue behavior of RC beams externally strengthened with SB-CFRP sheets. The model incorporates cyclic-dependent CFRP-concrete interface degradation. Existing experimental results are utilized to validate its accuracy. Computational analyses are undertaken to explore the effects of CFRP dimensions, load and prestress levels, and end-U-shaped wrapping on fatigue performance. A simple model is proposed to predict fatigue life considering load and prestress levels. The FE model effectively predicts fatigue performance. Parametric studies indicate that narrow CFRP strips are unable to prevent concrete failure under high loads. Fatigue failure modes include rebar ruptures and CFRP delamination. Besides, the end-U-shaped wrapping reduces interface damage, extending fatigue life. The study emphasizes the sensitivity of vibration excitation method to CFRP debonding. The proposed equation efficiently predicts the fatigue life of RC beams with externally bonded CFRP strips on their sides.

The 3d response of a large-scale masonry arch bridge - part I: Performance under low and medium loading levels

Masonry arch bridges are characterised by three-dimensional (3D) behaviour when subjected to external eccentric loading (e.g., vehicle loads). The arch ring, abutments, backfill and spandrel walls may interact with each other in a complex manner, leading to a 3D mode of response that can have a significant impact on the initiation and propagation of damage. However, there is a dearth of experimental data from tests designed to investigate the 3D behaviour of masonry arch bridges, particularly under loading levels below those required to cause failure. This paper presents results from tests on a large-scale brickwork masonry arch bridge subjected to low- and mid-level static loads under laboratory conditions. Point loads of increasing magnitude were applied at different locations on the top of the backfill in order to investigate 3D response and damage accumulation. Details of the experimental setup, material characterisation, and the results obtained from static and repeated load tests at low- and mid-level load magnitudes are presented herein. Results demonstrate that the bridge exhibited a 3D mode of response under eccentric point loads. Loading at the mid-span resulted in greater deformation of the arch barrel compared to loading at the quarter- and three-quarter-span points, due to the shallower backfill depth over the crown. Under the mid-level loading, stiffness degradation was observed during the testing regime, suggesting an accumulation of damage in the bridge. Moreover, when loading was applied close to a spandrel wall, measurable out-of-plane deformation of the spandrel wall was observed, with this deformation increasing significantly as the load was increased from 150 kN to 250 kN. This results from a combination of increased lateral soil pressure and decreased shear resistance at the arch-spandrel wall interface.

Spatio-temporal distribution and source contributions of the ambient pollutants in Lucknow city, India.

Clean air is imperative to the survival of all life forms on the planet. However, recent times have witnessed enormous escalation in urban pollution levels. It is therefore, incumbent upon us to decipher measures to deal with it. In perspective, the present study was carried out to assess PM10 and PM2.5 loading, metallic constituents, gaseous pollutants, source contributions, health impact and noise level of nine-locations, grouped as residential, commercial, and industrial in Lucknow city for 2019-21. Mean concentrations during pre-monsoon for PM10, PM2.5, SO2 and NO2 were: 138.2 ± 35.2, 69.1 ± 13.6, 8.5 ± 3.3 and 32.3 ± 7.4µg/m3, respectively, whereas post-monsoon concentrations were 143.0 ± 33.3, 74.6 ± 14.5, 12.5 ± 2.1, and 35.5 ± 6.3µg/m3, respectively. Exceedance percentage of pre-monsoon PM10 over National Ambient Air Quality Standards (NAAQS) was 38.2% while that for post-monsoon was 43.0%; whereas corresponding values for PM2.5 were 15.2% and 24.3%. Post-monsoon season showed higher particulate loading owing to wintertime inversion and high humidity conditions. Order of elements associated with PM2.5 is Co < Cd < Cr < Ni < V < Be < Mo < Mn < Ti < Cu < Pb < Se < Sr < Li < B < As < Ba < Mg < Al < Zn < Ca < Fe < K < Na and that with PM10 is Co < Cd < Ni < Cr < V < Ti < Be < Mo < Cu < Pb < Se < Sr < Li < B < As < Mn < Ba < Mg < Al < Fe < Zn < K < Na < Ca. WHO AIRQ + ascertained 1654, 144 and 1100 attributable cases per 0.1 million of population to PM10 exposure in 2019-21. Source apportionment was carried out using USEPA-PMF and resolved 6 sources with highest percent contributions including road dust re-entrainment, biomass burning and vehicular emission. It is observed that residents of Lucknow city regularly face exposure to particulate pollutants and associated constituents making it imperative to develop pollution abetment strategies.

P-757 An artificial intelligence model to predict upcoming patient oocyte collections to help optimize efficiency and safety in the embryology laboratory

Abstract Study question Can artificial intelligence (AI) be used to forecast the number of oocyte collections that will occur at a clinic multiple days in advance? Summary answer An AI model can accurately predict how many oocyte collections will occur across a clinic up to seven days in advance. What is known already There exists significant variability in the duration of ovarian stimulation for patients going through IVF, which can often lead to peaks and valleys of workload for the embryology laboratory. On a given day, a laboratory being under or over resourced can lead to poor utilization of resources or overtime hours. This is especially problematic as the demand for IVF steadily increases, particularly for large clinics doing thousands of oocyte collections (OC) per year. A tool to help predict clinic OC workload many days in advance could assist with laboratory staffing and operational efficiency through load leveling. Study design, size, duration Historical, de-identified electronic medical record data from 6140 patients undergoing ovarian stimulation at a large IVF clinic in the U.S. between January 2021 to January 2023 was collected. Patients who started treatment between January 2021 to December 2021 were used for training the AI model (N = 3126). The remaining patients were used for evaluating the model (N = 3014). Participants/materials, setting, methods A gradient boosting classifier (Catboost) was trained to predict a patient’s remaining cycle duration using E2, follicle sizes, and day of medication. This model outputs a probability that a patient’s OC will land on any specific future day. To predict the number of OC across a clinic on a future day, the model predicts the probability that each patient will have their retrieval on that day, and calculates the convolution to estimate total retrievals. Main results and the role of chance The clinic had an average of 7.9 OC per day. The OC projection accuracy was assessed by iterating through each date in the test dataset and predicting the number of OC each day over the next 7 days, for all patients undergoing stimulation who had not yet been triggered. In this analysis, the model predicted the total number of OC on each day with a mean absolute error of 1.56 retrievals and an R2 of 0.72. The model was able to identify days where workload exceeded 11 OC (80th percentile) with 86% accuracy and 58% precision. The model was able to identify days where workload was below 5 OC (20th percentile) with 95% accuracy and 91% precision. Limitations, reasons for caution This model was trained at a single clinic and evaluated retrospectively. Future work should assess model performance at clinics with varying patient throughput, and evaluate prospectively how this tool could assist with load leveling of OC volume. Wider implications of the findings An AI model can predict when patients will be triggered based on their medication and response to treatment. This tool can be used to forecast the total number of OC at a clinic up to 7 days in advance, which could help improve efficiency for embryology and clinical staff. Trial registration number not applicable

Early change of plasma Epstein-Barr virus DNA load and the viral lytic genome level could positively predict clinical outcome in recurrent or metastatic nasopharyngeal carcinoma receiving anti-programmed cell death 1 monotherapy

PurposePatients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials.MethodsPatients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined “EBV response” as 3 consecutive timepoints of load below 50% of baseline, and “EBV progression” as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples.ResultsWe found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171–0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS.ConclusionIn summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.

Dexamethasone treatment influences tendon healing through altered resolution and a direct effect on tendon cells

Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells.

Cardiovascular risk associated with changes in anticholinergic load on four different scales: a registry-based cohort study of geriatric outpatients.

Recent studies have shown that anticholinergic medications are associated with cardiovascular disease. Little is known about how discontinuation of anticholinergic medication affects this association. We investigated how baseline anticholinergic load and change in anticholinergic load associates with major adverse cardiovascular events (MACE) on four different scales. We included all geriatric outpatients aged 65 and older in Denmark between January 2011 and December 2018. Data were sourced from Danish national registries. Anticholinergic drug exposure was assessed at first contact to the outpatient clinic (baseline) and changes were assessed at 180days after outpatient contact. Anticholinergic scales were the CRIDECO Anticholinergic Load Scale, Anticholinergic Drugs Scale, Anticholinergic Cognitive Burden and a scale by the Danish Institute of Rational Pharmacotherapy. Multivariate analyses were conducted to investigate the 1- and 5-year risk of MACE by baseline anticholinergic load and changes in anticholinergic load after 180days. We included a total of 64 378 patients in the analysis of baseline anticholinergic load and 54 010 patients remained after 180days for inclusion in the analysis of change in anticholinergic load. At baseline the mean age was 81.7year (SD 7.5) and 68% were women. Higher level of anticholinergic load on any scale associated with greater risk of MACE in a dose response pattern. There were no association between reduction in anticholinergic load and risk of MACE. While anticholinergic load at baseline was associated with MACE, reducing anticholinergic load did not lower the risk of MACE indicating the association may not be causal.