Subsequent Sensitivity Research Articles

Dose mediates the protracted effects of adolescent THC exposure on reward and stress reactivity in males relevant to perturbation of the basolateral amygdala transcriptome.

Despite the belief that cannabis is relatively harmless, exposure during adolescence is associated with increased risk of developing several psychopathologies in adulthood. In addition to the high levels of use amongst teenagers, the potency of ∆-9-tetrahydrocannabinol (THC) has increased more than fourfold compared to even twenty years ago, and it is unclear whether potency influences the presentation of THC-induced behaviors. Expanded knowledge about the impact of adolescent THC exposure, especially high dose, is important to delineating neural networks and molecular mechanisms underlying psychiatric risk. Here, we observed that repeated exposure to low (1.5 mg/kg) and high (5 mg/kg) doses of THC during adolescence in male rats produced divergent effects on behavior in adulthood. Whereas low dose rats showed greater sensitivity to reward devaluation and also self-administered more heroin, high dose animals were significantly more reactive to social isolation stress. RNA sequencing of the basolateral amygdala, a region linked to reward processing and stress, revealed significant perturbations in transcripts and gene networks related to synaptic plasticity and HPA axis that were distinct to THC dose as well as stress. In silico single-cell deconvolution of the RNAseq data revealed a significant reduction of astrocyte-specific genes related to glutamate regulation in stressed high dose animals, a result paired anatomically with greater astrocyte-to-neuron ratios and hypotrophic astrocytes. These findings emphasize the importance of dose and behavioral state on the presentation of THC-related behavioral phenotypes in adulthood and dysregulation of astrocytes as an interface for the protracted effects of high dose THC and subsequent stress sensitivity.

Abstract P2-12-03: Phenotype shifting in early breast cancer with and without primary systemic treatment: A retrospective cohort analysis correlating core needle biopsies and excisional biopsies in 1250 consecutive real-world cases

Abstract Introduction: Breast cancer (BC) is a heterogenous disease, composed of various subclones with different response to treatment strategies, known as clonal sensitivity. PST might modulate the biology of BC cells and thus, the molecular subtype. In our single-center, retrospective cohort analysis we evaluated the concordance of the molecular subtype using ER, PR, HER2 status and Ki67 based on the core needle biopsies (CNB) and the excisional biopsies (EB) in primary, early breast cancer (eBC) with and without primary systemic treatment (PST). Finally, we analyzed the subtype shifting in residual tumors after PST.Methods: From January 1st, 2007 to December 31st, 2016 we identified a total of 1250 consecutive eBCs with corresponding samples from the CNB and the EB were analyzed. Upfront surgery after CNB was performed during the observational period in 1002 eBCs, allowing us to compare the histopathological findings of the CNB and the EB in pairs (cohort C1). PST followed by surgery was performed in 248 eBCs. A pathological complete response (pCR) was achieved in 60 cases. One patient with a clinical complete response (cCR) after PST, refused surgery and was excluded from the analysis. A non-pCR as best response was detected after the completion of PST in 187 eBCs, allowing us to compare the histopathological findings of the CNB and the EB in pairs (cohort C2). The analysis was performed separately in C1 and C2 and the final results were compared.Results: In C1 subtype shifting between CNB and EB in C1 was 18.2% for luminal A, 33.0% for luminal B HER2-, 27.8% for luminal B HER2+, 19.3% for HER2 enriched and 10.1% for basal like tumors. In C2, it was 31.5% for luminal A, 49.1% for luminal B HER2-, 39.0% for luminal B HER2+, 23.1% for HER2 enriched and 9.0% for basal like tumors. Regarding ER, PR, HER2 status and Ki67 we identified between CNB and EB in C1 the following discrepancies: 2.0%, 10.0%, 6.0%, 20.3% and in C2 the following treatment related changes: 8.3%, 27.1%, 11.4%, 52.1%. The number of CNBs had no influence on the changes above. Significant variations in subtype shifting based on PST were identified in C2 compared to C1.Conclusion: In C1 we demonstrated a high concordance of the prognostic factors, identified by one experienced pathologist, allowing us to validate the differences induced by PST. In C2 we demonstrated a significant phenotype shifting, which was dominated by the luminal B subtype. Besides fixational and observational issues, intratumoral heterogeneity of BC and the subsequent clonal sensitivity may explain our results. Present experimental data are suggesting that this treatment related changes might be transient in nature. Prospective data will clarify, if this observation might be therapy relevant, or if the subclones dominating the residual tumor in non-pCR require new post-neoadjuvant treatment approaches. Molecular Subtypes in CNB and EB with and without PSTLuminal ALuminal B HER2-Luminal B HER2+HER2 enrichedBasal likeC1CNB59.1%24.8%6.9%3.4%5.8%EB56.0%26.0%8.7%3.5%5.8%C2CNB22.6%34.2%23.8%7.2%12.2%EB50.4%29.2%17.4%6.7%16.3% Citation Format: Athanasios Argyriadis, Michael Bange, Keyur Mehta, Sibylle Loibl, Silvia Khodaverdi, Susanne Braun, Carsten Denkert, Christian Jackisch. Phenotype shifting in early breast cancer with and without primary systemic treatment: A retrospective cohort analysis correlating core needle biopsies and excisional biopsies in 1250 consecutive real-world cases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-03.

Performance analysis of a novel compression-assisted absorption power and refrigeration system with selected 1,1-difluoroethane/ionic liquid

Low global warming potential hydrofluorocarbon (HFC)-ionic liquid (IL) mixtures are a promising type of environmentally friendly binary working pair that can overcome the drawbacks of traditional mixtures. To compensate for the high-grade power consumption of its applicable compression-assisted absorption refrigeration systems, a novel combined absorption system with a compression booster for the cogeneration of power and refrigeration (CAPRC) is proposed via this study. The system operates efficiently by utilizing low-grade heat sources in a cascaded manner. It was studied using energy, exergy, and economic analyses with verified models. 1,1-difluoroethane/1-hexyl-3-methylimidazolium bis(triflfluoromethylsulfonyl)imide was first pre-selected from potential working pairs due to its superior thermodynamic properties and highest performances in absorption systems. The performances of the CAPRC under typical space-cooling conditions were then analyzed theoretically for various operating modes and control parameters. Noted in cold mode, CAPRC could produce a constant cooling load by enhancing the utilization of heat sources through the adjustment of compression ratio and expansion ratio, indicating its outstanding adaptability to time-variable low-grade heat sources. The CAPRC could also generate 80.91% more net power than the reference system and offered 12.87% and 10.68% higher effective energy and exergy efficiencies, respectively, under optimized base-case control parameters in dual-output mode. A subsequent sensitivity analysis was conducted to assess its power and cooling production and effective efficiencies under various external conditions. The shortest payback period was finally estimated to be 6.43 years, which is 19.28% less than the reference system, further demonstrating the cost-effectiveness of the proposed system.

Benefit and risk evaluation of inland nuclear generation investment in Kazakhstan combined with an analytical MGT method

Purpose In the process of building the “Belt and Road” and “Bright Road” community of interests between China and Kazakhstan, this paper proposes the construction of an inland nuclear power plant in Kazakhstan. Considering the uncertainty of investment in nuclear power generation, the authors propose the MGT (Monte-Carlo and Gaussian Radial Basis with Tensor factorization) utility evaluation model to evaluate the risk of investment in nuclear power in Kazakhstan and provide a relevant reference for decision making on inland nuclear investment in Kazakhstan. Design/methodology/approach Based on real options portfolio combined with a weighted utility function, this study takes into account the uncertainties associated with nuclear power investments through a minimum variance Monte Carlo approach, proposes a noise-enhancing process combined with geometric Brownian motion in solving complex conditions, and incorporates a measure of investment flexibility and strategic value in the investment, and then uses a deep noise reduction encoder to learn the initial values for potential features of cost and investment effectiveness. A Gaussian radial basis function used to construct a weighted utility function for each uncertainty, generate a minimization of the objective function for the tensor decomposition, and then optimize the objective loss function for the tensor decomposition, find the corresponding weights, and perform noise reduction to generalize the nonlinear problem to evaluate the effectiveness of nuclear power investment. Finally, the two dimensions of cost and risk (estimation of investment value and measurement of investment risk) are applied and simulated through actual data in Kazakhstan. Findings The authors assess the core indicators of Kazakhstan's nuclear power plants throughout their construction and operating cycles, based on data relating to a cluster of nuclear power plants of 10 different technologies. The authors compared it with several popular methods for evaluating the benefits of nuclear power generation and conducted subsequent sensitivity analyses of key indicators. Experimental results on the dataset show that the MGT method outperforms the other four methods and that changes in nuclear investment returns are more sensitive to changes in costs while operating cash flows from nuclear power are certainly an effective way to drive investment reform in inland nuclear power generation in Kazakhstan at current levels of investment costs. Research limitations/implications Future research could consider exploring other excellent methods to improve the accuracy of the investment prediction further using sparseness and noise interference. Also consider collecting some expert advice and providing more appropriate specific suggestions, which will facilitate the application in practice. Practical implications The Novel Coronavirus epidemic has plunged the global economy into a deep recession, the tension between China and the US has made the energy cooperation road unusually tortuous, Kazakhstan in Central Asia has natural geographical and resource advantages, so China–Kazakhstan energy cooperation as a new era of opportunity, providing a strong guarantee for China's political and economic stability. The basic idea of building large-scale nuclear power plants in Balkhash and Aktau is put forward, considering the development strategy of building Kazakhstan into a regional international energy base. This work will be a good inspiration for the investment of nuclear generation. Originality/value This study solves the problem of increasing noise by combining Monte Carlo simulation with geometric Brownian motion under complex conditions, adds the measure of investment flexibility and strategic value, constructs the utility function of noise reduction weight based on Gaussian radial basis function and extends the nonlinear problem to the evaluation of nuclear power investment benefit.

Uncertainty Analysis of Parameters in SST Turbulence Model for Shock Wave-Boundary Layer Interaction

Shock wave-boundary layer interactions (SWBLIs) have a tremendous influence on the performance of hypersonic vehicles. For the numerical simulation of such engineering flows, Reynolds averaged Navier-Stokes (RANS) still occupies an irreplaceable role. However, parameters of turbulence models in RANS have substantial uncertainties, which impact the reliability of simulation results. Thus, the aim of the present study is to conduct an uncertainty analysis on parameters in the shear-stress transport (SST) turbulence model for the simulation of SWBLIs. In the current work, uncertainty quantification was performed first. A surrogate model was constructed by the non-intrusive polynomial chaos (NIPC) method to propagate uncertainties from model parameters to the quantities of interests (QoIs) and quantify them. In the subsequent sensitivity analysis, the key parameters were identified for such flow by calculating the Sobol index of each parameter for various QoIs. The results indicate that uncertainties of model parameters led to non-negligible uncertainties in those QoIs, particularly in skin friction and wall heat flux. The parameters α1, σω1, β1 were identified as primary contributors through the sensitivity analysis. Moreover, the specific effects of the three parameters on the flow prediction were analyzed by changing the parameters’ values separately.

Comparison of Gated Recurrent Unit vs. Mixture Density Network in Insulin Sensitivity Prediction

There are several methods for the prediction of future values of a time series, or in general, for the probability density prediction problem. In this paper two neural network prediction models are compared: Mixture Density Network (MDN) and Gated Recurrent Unit (GRU) in the prediction of the insulin sensitivity (SI) of a patient under intensive care.The basic difference between the two methods is that while MDN is a stateless network model the GRU is a stateful model. In the study, both of the models predict the probability density function of the future SI value, but the MDN considers the physiological process like a Markov-chain: the future SI value depends lowly on the previous value. In contrast, the GRU model attempts to model the longer-term dependencies between subsequent SI values in its internal states and improve the prediction accuracy based on the information derived from the previous SI values.In the study we have found that the GRU implemented stateful prediction improved the prediction accuracy by 10 percent, showing the prediction power of the GRU model in physiological problems and proving the existence of longer-term dependencies in the SI time series. These outcomes confirm previously published results showing that the insulin sensitivity prediction can be improved considering the longer-term history of the patients.

Determining Air Traffic Controller Proficiency: Identifying Objective Measures Using Clustering

Air traffic control (ATC) is a complex and demanding job reserved for highly-trained professionals. Training ATC candidates is challenging as trainees are subjectively assessed by instructors who are biased by their own ways of working. As an effort to determine control expertise objectively, this study employed clustering techniques on an existing data set in which course and professional controllers participated in a medium-fidelity simulation experiment. Results identified a set of eight measures that formed two distinct and stable expertise clusters. A subsequent sensitivity analysis was able to reveal how far (or close) each course participant was positioned from the expert cluster and on which measures those participants deviated from the experts. At this stage, however, it is difficult to translate these results into specific advice on how to improve underdeveloped skills. Despite the small sample size and limited generalizability of the results in this exploratory study, the method appears to be a promising demonstration in determining objective factors that describe ATC expertise, warranting further research.

Effects of States’ Laws on Youth Physical Activity Participation and Obesity Prevalence

The alarming prevalence of obesity and lack of physical activity among adolescents led to immediate policy action to address these concerns. Accordingly, many states introduced and enacted their own legislation to encourage physical activity in schools. Few studies have explored the effectiveness of the new legislation, however, especially at the state level. To answer the fundamental question of whether policy is effective and to describe the varying effects of state obesity policies, this study analyzed the Youth Risk Behavior Surveillance System from 2007 to 2017. Using the difference-in-differences method, this study found that legislative efforts to encourage physical activity had a significant and substantial effect on enhancing physical-activity participation and reducing adolescent obesity; however, subgroup analyses revealed that the effect was concentrated on female and white adolescents only. Additionally, the subsequent sensitivity analysis revealed that since 2015, when national attention started to divert to new health concerns (opioid abuse, for example), physical activity levels pulled back to 2009 levels. Rates of obesity and overweight have been on a sharp rise again since 2015. Lawmakers should reconsider changes in the law merging physical environments with digital environments, particularly for members of Generation Alpha, who will have ever more enticements for screen time.

Severe irritant contact dermatitis from olanexidine gluconate and subsequent skin sensitization

Severe irritant contact dermatitis from olanexidine gluconate and subsequent skin sensitization

Financial Analysis of Water Management Practices in Cranberry Production in Quebec, Canada

At a global scale, Canada is the second largest cranberry producer, with Quebec being the largest producing region within Canada. Efficient water use in agricultural production has long been a topic of outmost importance to agricultural producers, and governing bodies. The immediacy of climate change effects sped up the need to find solutions that conserve water. One such promising technology is irrigation using real-time tensiometers, which provides rapidly critical irrigation needs information to producers. Adoption of improved technologies by farmers is dependent on the effect it has on the farms’ bottom line. In this study, we examine the financial performance of real-time tensiometer based irrigation, and compare it to evaporation needs based irrigation (baseline), in the context of a Quebec-based cranberry farm. Our findings show that irrigating using real-time tensiometers technology generated higher economic returns. With a net present value of $96,847, this technology increased returns by nearly 53% compared to the baseline technology. Subsequent sensitivity analyses confirmed the robustness of these findings, even when changing important farming parameters.

Satellite Retrieval of Microwave Land Surface Emissivity under Clear and Cloudy Skies in China Using Observations from AMSR-E and MODIS

Microwave land surface emissivity (MLSE) is an important geophysical parameter to determine the microwave radiative transfer over land and has broad applications in satellite remote sensing of atmospheric parameters (e.g., precipitation, cloud properties), land surface parameters (e.g., soil moisture, vegetation properties), and the parameters of interactions between atmosphere and terrestrial ecosystem (e.g., evapotranspiration rate, gross primary production rate). In this study, MLSE in China under both clear and cloudy sky conditions was retrieved using satellite passive microwave measurements from Aqua Advanced Microwave Scanning Radiometer-Earth Observing System (AMSR-E), combined with visible/infrared observations from Aqua Moderate Resolution Imaging Spectroradiometer (MODIS), and the European Centre for Medium-Range Weather Forecasts (ECMWF) atmosphere reanalysis dataset of ERA-20C. Attenuations from atmospheric oxygen and water vapor, as well as the emissions and scatterings from cloud particles are taken into account using a microwave radiation transfer model to do atmosphere corrections. All cloud parameters needed are derived from MODIS visible and infrared instantaneous measurements. Ancillary surface skin temperature as well as atmospheric temperature-humidity profiles are collected from ECMWF reanalysis data. Quality control and sensitivity analyses were conducted for the input variables of surface skin temperature, air temperature, and atmospheric humidity. The ground-based validations show acceptable biases of primary input parameters (skin temperature, 2 m air temperature, near surface relative humidity, rain flag) for retrieving using. The subsequent sensitivity tests suggest that 10 K bias of skin temperature or observed brightness temperature may result in a 4% (~0.04) or 7% (0.07) retrieving error in MLSE at 23.5 GHz. A nonlinear sensitivity in the same magnitude is found for air temperature perturbation, while the sensitivity is less than 1% for 300 g/m2 error in cloud water path. Results show that our algorithm can successfully retrieve MLSE over 90% of the satellite detected land surface area in a typical cloudy day (cloud fraction of 64%), which is considerably higher than that of the 29% area by the clear-sky only algorithms. The spatial distribution of MLSE in China is highly dependent on the land surface types and topography. The retrieved MLSE is assessed by compared with other existing clear-sky AMSR-E emissivity products and the vegetation optical depth (VOD) product. Overall, high consistencies are shown for the MLSE retrieved in this study with other AMSR-E emissivity products across China though noticeable discrepancies are observed in Tibetan Plateau and Qinling-Taihang Mountains due to different sources of input skin temperature. In addition, the retrieved MLSE exhibits strong positive correlations in spatial patterns with microwave vegetation optical depth reported in the literature.

The Use of Machine Learning Models in Estimating the Compressive Strength of Recycled Brick Aggregate Concrete

The focus of this study is to investigate the applicability of Adaptive Neuro-Fuzzy Inference System (ANFIS), Artificial Neural Network (ANN), and Multiple Linear Regression (MLR) in modeling the compressive strength of Recycled Brick Aggregate Concrete (RBAC). A comparative study on the application of the aforementioned models is developed based on statistical tools such as coefficient of determination, mean absolute error, root mean squared error, and some others, and the application potential of each of these models is investigated. To study the effects of RBAC factors on the performance of representative data-driven models, the Sensitivity Analysis (SA) method is used. The findings revealed that ANN with R2 value of 0.9102 has a great application potential in predicting the compressive strength of concrete. In the absence of ANN, ANFIS with R2 value of 0.8538 is also an excellent substitute for predictions. MLR was shown to be less effective than the preceding models and is only recommended for preliminary estimations. In addition, Subsequent sensitivity analysis on the database indicates the reliability of the prediction models have a strong correlation to the number of input parameters. The application of ANN and ANFIS as a precursor to traditional methods can eliminate the need for old-style tests, thus, constituting a significant reduction in time and expense needed for design and/or repairs.

EETs/sEHi alleviates nociception by blocking the crosslink between endoplasmic reticulum stress and neuroinflammation in a central poststroke pain model

BackgroundCentral post-stroke pain (CPSP) is a chronic and intolerable neuropathic pain syndrome following a cerebral vascular insult, which negatively impacts the quality of life of stroke survivors but currently lacks efficacious treatments. Though its underlying mechanism remains unclear, clinical features of hyperalgesia and allodynia indicate central sensitization due to excessive neuroinflammation. Recently, the crosslink between neuroinflammation and endoplasmic reticulum (ER) stress has been identified in diverse types of diseases. Nevertheless, whether this interaction contributes to pain development remains unanswered. Epoxyeicosatrienoic acids (EETs)/soluble epoxy hydrolase inhibitors (sEHi) are emerging targets that play a significant role in pain and neuroinflammatory regulation. Moreover, recent studies have revealed that EETs are effective in attenuating ER stress. In this study, we hypothesized that ER stress around the stroke site may activate glial cells and lead to further inflammatory cascades, which constitute a positive feedback loop resulting in central sensitization and CPSP. Additionally, we tested whether EETs/sEHi could attenuate CPSP by suppressing ER stress and neuroinflammation, as well as their vicious cycle, in a rat model of CPSP.MethodsYoung male SD rats were used to induce CPSP using a model of thalamic hemorrhage and were then treated with TPPU (sEHi) alone or in combination with 14,15-EET or 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, the EET antagonist), tunicamycin (Tm, ER stress inducer), or 4-PBA (ER stress inhibitor). Nociceptive behaviors, ER stress markers, JNK and p38 (two well-recognized inflammatory kinases of mitogen-activated protein kinase (MAPK) signaling) expression, and glial cell activation were assessed. In addition, some healthy rats were intrathalamically microinjected with Tm or lipopolysaccharide (LPS) to test the interaction between ER stress and neuroinflammation in central pain.ResultsAnalysis of the perithalamic lesion tissue from the brain of CPSP rats demonstrated decreased soluble epoxy hydrolase (sEH) expression, which was accompanied by increased expression of ER stress markers, including BIP, p-IRE, p-PERK, and ATF6. In addition, inflammatory kinases (p-p38 and p-JNK) were upregulated and glial cells were activated. Intrathalamic injection of sEHi (TPPU) increased the paw withdrawal mechanical threshold (PWMT), reduced hallmarks of ER stress and MAPK signaling, and restrained the activation of microglia and astrocytes around the lesion site. However, the analgesic effect of TPPU was completely abolished by 14,15-EEZE. Moreover, microinjection of Tm into the thalamic ventral posterior lateral (VPL) nucleus of healthy rats induced mechanical allodynia and activated MAPK-mediated neuroinflammatory signaling; lipopolysaccharide (LPS) administration led to activation of ER stress along the injected site in healthy rats.ConclusionsThe present study provides evidence that the interaction between ER stress and neuroinflammation is involved in the mechanism of CPSP. Combined with the previously reported EET/sEHi effects on antinociception and neuroprotection, therapy with agents that target EET signaling may serve as a multi-functional approach in central neuropathic pain by attenuating ER stress, excessive neuroinflammation, and subsequent central sensitization. The use of these agents within a proper time window could not only curtail further nerve injury but also produce an analgesic effect.

Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma

BackgroundIn the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL).MethodsPrimary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor.ResultsThe initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56–3.49] and 1.21 [0.56–2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44–1.49] and 0.95 [0.58–1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01–0.07] and 0.08 [0.01–0.67], respectively) and study-specific neurological events (0.16 [0.08–0.33] and 0.05 [0.02–0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor.ConclusionsAfter matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL.Trial registration: NCT02631044 and NCT02348216

Potential of surrogate modelling in compressor casing design focussing on rapid tip clearance assessments

ABSTRACTLosses induced by tip clearance limit decisive improvements in the system efficiency and aerodynamic operational stability of aero-engine axial compressors. The tendency towards even lower blade heights to compensate for higher fluid densities aggravates their influence. Generally, it is emphasised that the tip clearance should be minimised but remain large enough to prevent collisions between the blade tip and the casing throughout the entire mission. The present work concentrates on the development of a preliminary aero-engine axial compressor casing design methodology involving meta-modelling techniques. Previous research work at the Institute for Turbomachinery and Flight Propulsion resulted in a Two-Dimensional (2D) axisymmetric finite element model for a generic multi-stage high-pressure axial compressor casing. Subsequent sensitivity studies led to the identification of significant parameters that are important for fine-tuning the tip clearance via specific flange design. This work is devoted to an exploration of the potential of surrogate modelling in preliminary compressor casing design with respect to rapid tip clearance assessments and its corresponding precision in comparison with finite element results. Reputed as data-driven mathematical approximation models and conceived for inexpensive numerical simulation result reproduction, surrogate models show even greater capacity when linked with extensive design space exploration and optimisation algorithms.Compared with high-fidelity finite element simulations, the reductions obtained in computational time when using surrogate models amount to 99.9%. Validated via statistical methods and dependent on the size of the training database, the precision of surrogate models can reach down to the range of manufacturing tolerances. Subsequent inclusion of such surrogate models in a parametric optimisation process for tip clearance minimisation rapidly returned adaptions of the geometric design variables.

Induction of Ticlike Involuntary Movements in Rats by Striatotomy and Subsequent Neurochemical Sensitization

It has been proposed that Tourette syndrome is associated with dysfunction in widespread cortical areas and globus pallidus externus hyperactivity secondary to dopaminergic hyperactivity and serotonergic/dynorphinergic hypoactivity. The main objective of this study was to test this hypothesis by developing an animal model of Tourette syndrome via striatotomy, followed by administration of drugs that mimic the neurotransmitter environment, so as to induce globus pallidus externus hyperactivity. Rats were assigned to 3 groups: stereotactic striatotomy (STT) and striatal sham -lesion (SHAM) groups, treated with anterior and posterior striatum procedures in both hemispheres, and a group of nonoperated animals (NAIVE). Postoperatively, all rodents were blindly administered 3 drug protocols: levodopa/benserazide; levodopa/benserazide/ergotamine/naloxone (MIX); and saline. The animals were filmed at the peak action of these drugs. The videos were evaluated by a single blinded researcher. Six types of involuntary movements (IMs) were observed: cephalic, trunk jerks, oromandibular, forepaw jerks, dystonic, and locomotive. The number of animals with IM and the mean number of IM after both levodopa/benserazide and MIX was significantly higher in the STT compared with the SHAM and NAIVE groups. In the SHAM and NAIVE, MIX was superior to levodopa/benserazide in the induction of IM. In the STT, MIX was superior to levodopa/benserazide in the induction of trunk jerks. Appendicular IM were more common after posterior than after anterior striatotomy. These results show that striatotomy, followed by administration of levodopa/benserazide alone or associated with ergotamine and naloxone, is efficacious in inducing IM, supporting the hypothesis that led to this study.

Desensitization of human breast progenitors by a transient exposure to pregnancy levels of estrogen

Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer. Because hormone receptor positive progenitors in the human breast relay endocrine signaling, we here sought to determine whether an experimental mimicry of the third trimester surge of hormones would change their susceptibility to growth stimulation. Hormone receptor positive, reduction mammoplasty-derived human breast epithelial progenitors were exposed to a short-term, pregnancy-level of estradiol, and their subsequent response to estradiol stimulation was analyzed. Exposure to pregnancy-level of estradiol results in subsequent lower sensitivity to estrogen-induced proliferation. Expression array and immunoblotting reveal upregulation of S100A7 and down-regulation of p27, both associated with parity and epithelial differentiation. Notably, we find that the epithelial differentiation is accompanied by upregulation of E-cadherin and down-regulation of vimentin as well as by diminished migration and more mature luminal epithelial differentiation in a mouse transplantation model. Our findings are in support of a de-sensitization mechanism for pregnancy-induced prevention against breast cancer.

Mixed layer water mass analysis on the East China Sea inner shelf

We present a new extension of the traditional mixing triangle water mass analysis that is adapted for the mixed layer (ML) by including the atmospheric effects as a correction term in the original equations. The ML water mass analysis is then employed to determine the water mass contributions in the Changjiang river plume area based on observed hydrographic data in winter, summer and autumn of 2018. The comparison with the traditional method shows remarkable difference in the ratio between the Taiwan Strait Warm Water (TSWW) and the Kuroshio Subsurface Water (KSSW). In winter, a non-neglectable portion of TSWW is found east of 123°E, possibly due to the relaxation of the northeastern monsoon in March. In summer, both methods show that the upper ML water is mostly originated from TSWW and the lower layer from KSSW. The percentage of TSWW is however smaller with the new method. A second experiment using the Kuroshio Surface Water (KSW) in place of the KSSW reveals that the KSW intrusion is not evident in this region. During autumn, TSWW accounts for a major portion of the intrusion, and the cold and salty KSSW is only observed in the bottom layer below 50 m. The subsequent error analysis and sensitivity tests regarding to the relevant input parameters demonstrate the reliability and robustness of this new ML water mass analysis, but dynamic studies are still needed to fully understand the seasonal characteristics of the intrusion into the East China Sea shelf.

Brain Metastases Status and Immunotherapy Efficacy in Advanced Lung Cancer: A Systematic Review and Meta-Analysis.

BackgroundBrain metastases (BMs) indicate poor outcomes and are commonly excluded in immunotherapy clinical trials in advanced lung cancer; moreover, the effect of BM status on immunotherapy efficacy is inconsistent and inconclusive. Therefore, we conducted a meta-analysis to assess the influence of BM status on immunotherapy efficacy in advanced lung cancer.MethodsElectronic databases and all major conference proceedings were searched without language restrictions according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We extracted randomized clinical trials on lung cancer immunotherapy that had available overall survival (OS) and/or progression-free survival (PFS) data based on the BM status. All analyses were performed using random effects models.ResultsFourteen randomized clinical trials with 9,089 patients were identified. Immunotherapy conferred a survival advantage to BM patients [OS-hazard ratio (HR), 0.72; 95% confidence interval (CI), 0.58–0.90; P = 0.004; and PFS-HR, 0.68; 95% CI, 0.52–0.87, P = 0.003]. Non-BM patients could also derive a survival benefit from immunotherapy (OS-HR, 0.76; 95% CI, 0.71–0.80; P <0.001; and PFS-HR, 0.68; 95% CI, 0.56–0.82, P <0.001). The pooled ratios of OS-HRs and PFS-HRs reported in BM patients versus non-BM patients were 0.96 (95% CI, 0.78–1.18; P = 0.72) and 0.97 (95% CI, 0.79–1.20; P = 0.78), respectively, indicating no statistically significant difference between them. Subsequent sensitivity analyses did not alter the results. Subgroup analyses according to tumor type, line of therapy, immunotherapy type, study design, and representation of BM patients reconfirmed these findings.ConclusionWe demonstrated that BM status did not significantly influence the immunotherapy efficacy in lung cancer, suggesting that both BM and non-BM patients could obtain comparable benefits.Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier (CRD42020207446).

Effect of time and spatial domains on monolayer 2D material interface thermal conductance measurement using ns ET-Raman

Raman-based approaches to characterizing thermal properties of nanoscale and microscale materials have proven to be powerful experimental methods. This work explores the potential of energy-transport state-resolved Raman (ET-Raman) for the precise determination of interfacial thermal conductance (G) between monolayer 2D materials and their substrates. ET-Raman employs a continuous wave laser and nanosecond (ns) pulsed laser to induce both steady state and transient heating while simultaneously collecting 2D material temperature information from the Raman signal. A 3D numerical model built using the finite volume method simulates the two differentiated thermal transport processes. The simulated temperature rises are compared with experimental Raman temperature information to extract G. In this study, we investigate the temporal effects of the pulse frequency and pulse width of the ns laser on precise characterization of G. By running multiple simulations for a range of pulsed laser frequencies and pulse widths, we determine that ET-Raman is most sensitive to precise interfacial thermal conductance measurements with short pulse widths (~below 20 ns) and with pulsing frequencies that ensure sufficient cooling time between consecutive pulses (~below 500 kHz). We also conclude that substrate thickness and laser spot size play critical roles in heat distribution and subsequent sensitivity to meaningful G measurements. As both laser spot size and SiO2 substrate thickness decrease, detection of interfacial thermal transport becomes more difficult. These results offer essential guidance in the design of future Raman-based approaches to thermal measurements using pulsed lasers.