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Background: Immune checkpoint inhibitors (ICIs) have been successfully used in the previous decade for the treatment of a variety of malignancies. Adverse events (AEs) can cause many symptoms, most notably cardiac. We analyzed the frequency of these adverse events, comparing pembrolizumab and other ICIs. Methods: Using the Food and Drug Administration (FDA) adverse event reporting database (FAERS), we searched for all adverse events of interest reported for every ICI included in this study. After obtaining the data, we conducted a disproportionality analysis using the reporting odds ratio (ROR) and the information component (IC). Results: A total of 6719 ICI-related cardiac adverse events of interest were reported in the database. Serious outcomes were reported in 100% of the cases, with 34.3% of the cases ending fatally. Compared with all other medications in the database, pembrolizumab use was more frequently associated with myocarditis, pericardial disease, heart failure, and atrial fibrillation. No difference was found in cardiotoxicity between different ICIs. Conclusions: Although infrequent, cardiac AEs in pembrolizumab use are associated with serious outcomes and high mortality. Prospective studies are needed to further research the connection between ICI use and cardiotoxicity.

Cilial pumping is a potent mechanism used to control and manipulate fluids on microscales. Recently, we introduced an electronically driven μ-cilial platform that can create arbitrary flow patterns in liquids near a surface with the potential for various engineering applications. This μ-cilial platform, however, utilized the coupling between elasticity and viscous drag to obtain pumping and had several limitations. For example, each cilium could only pump in one direction. Thus, to create bidirectional flows, it was necessary to fabricate and separately actuate two oppositely facing cilia. As another example, the generation of non-reciprocal cilial motions, a necessary condition for pumping at these scales, could only be achieved by matching the elastic stresses inherent in actuating the cilia with the viscous drag forces generated by the flows. This criterion severely restricted the frequency range over which the cilia could be operated and resulted in a small swept area, both of which restricted the volume of fluid being pumped in each cycle. These limitations contrast with the capabilities of natural cilia, which can achieve omnidirectional transport and operation over a broad range of frequencies. In natural cilia, these capabilities arise from their complex internal structure. Inspired by this strategy we designed hinged cilia and show they can achieve bidirectional pumping of larger fluid volumes over a broad range of frequencies. Finally, we demonstrate that even regular arrays of individually controlled hinged cilia can generate a variety of flow patterns using fewer cilia than in previous cilia metasurface designs. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have been successfully used in the previous decade for the treatment of a variety of malignancies. Adverse events (AEs) can cause many symptoms, most notably cardiac. We analyzed the frequency of these adverse events, comparing pembrolizumab and other ICIs. Methods: Using the Food and Drug Administration (FDA) adverse event reporting database (FAERS), we searched for all adverse events of interest reported for every ICI included in this study. After obtaining the data, we conducted a disproportionality analysis using the reporting odds ratio (ROR) and the information component (IC). Results: A total of 6719 ICI-related cardiac adverse events of interest were reported in the database. Serious outcomes were reported in 100% of the cases, with 34.3% of the cases ending fatally. Compared with all other medications in the database, pembrolizumab use was more frequently associated with myocarditis, pericardial disease, heart failure, and atrial fibrillation. No difference was found in cardiotoxicity between different ICIs. Conclusions: Although infrequent, cardiac AEs in pembrolizumab use are associated with serious outcomes and high mortality. Prospective studies are needed to further research the connection between ICI use and cardiotoxicity. [ABSTRACT FROM AUTHOR]

Background: Hot flashes are a common side effect of endocrine therapy (ET) that contribute to poor quality of life and decreased treatment adherence. Methods: Patients with breast cancer wo were receiving ET and experiencing hot flashes were enrolled through three parallel, randomized trials conducted in the United States, China, and South Korea. Participants were randomized to either immediate acupuncture (IA) or delayed acupuncture control (DAC). IA participants received 20 acupuncture sessions over 10 weeks, whereas DAC participants received usual care, then crossed over to acupuncture with a reduced intensity. The primary end point was a change in score on the endocrine symptom subscale of the Functional Assessment of Cancer Therapy (FACT)‐Endocrine Symptoms between baseline and week 10. Secondary end points included the hot flash score and the FACT‐Breast score. A planned pooled analysis of individual patient data was performed using longitudinal mixed models. Results: In total, 158 women with stage 0–III breast cancer were randomized (United States, n = 78; China, n = 40; South Korea, n = 40). At week 10, IA participants reported statistically significant improvements in the endocrine symptom subscale score (mean change ± standard error: 5.1 ± 0.9 vs. 0.2 ± 1.0; p =.0003), the hot flash score (−5.3 ± 0.9 vs. −1.4 ± 0.9; p <.003), and the FACT‐Breast total score (8.0 ± 1.6 vs. −0.01 ± 1.6; p =.0005) compared with DAC participants. The effect of the acupuncture intervention differed by site (p =.005). Conclusions: Acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer‐specific quality of life in women undergoing ET for breast cancer in the United States, China, and South Korea. In a pooled analysis of three parallel trials, acupuncture significantly reduced hot flashes and other endocrine symptoms in women with stage 0–III breast cancer undergoing endocrine therapy in the United States, China, and South Korea. In the women studied, acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer‐specific quality of life. [ABSTRACT FROM AUTHOR]

This paper presents a model for determining fuzzy evaluations of partial indicators of the availability of continuous systems at coal open pits using a neuro-fuzzy inference system. The system itself is a combination of fuzzy logic and artificial neural networks. The system availability is divided into partial indicators. By combining the fuzzy logic and artificial neural networks, a model is obtained that has the ability to learn and uses expert judgment for that learning. This paper deals with the ECC system (bucket wheel excavator-conveyor-crushing plant) of the open pit Drmno-Kostolac, which operates within the Electric Power Company of Serbia. The advantage of a model of this type is that it does not rely on the historical experiences of experts and usual predicted values for the fuzzy evaluation of partial indicators, which are based on the assumption that similar systems affect availability in a similar way. The fuzzy evaluation of partial indicators is based on historical data for the specific system for which the model was created. As such, it can more accurately predict continuous systems availability on the basis of expert evaluations in the appropriate time period. Another advantage of this model is that the availability is estimated on a quarterly basis, which gives a more accurate view because it uses a smaller time period with more similar characteristics and, thus, includes certain external influences which are related to the quarterly meteorological conditions.

This paper presents the model for the identification of reference points on the lifetime curve of engineering systems. This curve commonly represents the increase and decline of failure in relation to time. A direct correlation between failure rate and costs is assumed in this paper, therefore, statistical and empirical analysis of costs provided reference points. This approach is used for positioning stages of the engineering system’s lifetime with a minimal number of failures and costs, regardless of whether these are acceptable or not. The following three stages are usually identified: the beginning, the stationary part and the end of life. The boundaries between them are recognized on the basis of minimum total lifetime costs and on economic lifetime costs. Model is tested on the dozers, machines frequently used in the mining industry for the earthmoving operations, and which are characterized by high operating and maintenance costs.

This work presents a model for determining the availability of continuous systems at open pits by applying fuzzy logic and fuzzy inference systems. The applied model was formed by the synthesis of independent partial indicators of availability. The model is based on an expert system for assessing the availability of continuous mining systems. The availability of the system, as a complex state parameter, is decomposed into the partial indicators, reliability, and convenience of maintenance, and the fuzzy compositions, used for integration the partial indicators, are the max–min and min–max compositions. The advantage of this model in comparison to the conventional models is that it takes into account the effect of practical indicators of availability, does not require long-term monitoring, and records necessary to determine the time picture of the system state. This model for determining the availability has a role to help responsible persons at open pits in the planning and control of exploitation, and the adoption of an appropriate maintenance strategy, all with the aim of stable production and cost reduction. The presented model can be used as a tool for the quick assessment of system availability, based on expert judgments and assessments.

The generation of human hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) represents a major goal in regenerative medicine and is believed would follow principles of early development. HSCs arise from a type of endothelial cell called a “hemogenic endothelium” (HE), and human HSCs are experimentally detected by transplantation into SCID or other immune-deficient mouse recipients, termed SCID-Repopulating Cells (SRC). Recently, SRCs were detected by forced expression of seven transcription factors (TF) (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1, and SPI1) in hPSC-derived HE, suggesting these factors are deficient in hPSC differentiation to HEs required to generate HSCs. Here we derived PECAM-1-, Flk-1-, and VE-cadherin-positive endothelial cells that also lack CD45 expression (PFVCD45−) which are solely responsible for hematopoietic output from iPSC lines reprogrammed from AML patients. Using HEs derived from AML patient iPSCs devoid of somatic leukemic aberrations, we sought to generate putative SRCs by the forced expression of 7TFs to model autologous HSC transplantation. The expression of 7TFs in hPSC-derived HE cells from an enhanced hematopoietic progenitor capacity was present in vitro, but failed to acquire SRC activity in vivo. Our findings emphasize the benefits of forced TF expression, along with the continued challenges in developing HSCs for autologous-based therapies from hPSC sources.

The risk assessment of engineering systems represents an important part of the quality of service and dependability. The existing methods for risk evaluation use crisp sets for rating partial indicators’ proposition and their cumulative products as an overall indicator. In this paper, existing FMEA and FMECA methods have been improved using the fuzzy expert system for calculating the risk priority number. The application of fuzzy logic allows the use of linguistic descriptions for risk analysis. In this way, the state of the system in terms of risks and consequences is better described. The settings of the fuzzy systems are based on the application of two multi-criteria decision-making methods. The AHP method was used to define the mutual relationship of the impact of partial indicators (occurrence, severity, and detectability) on risk. In this way, subjectivity in risk assessment is reduced. In the composition of the fuzzy model, the TOPSIS method is introduced to reduce the dissipation of results, which contributes to the accuracy of the outcome. This contributes to the accuracy of the results. The results were verified through a case study of a complex engineering system—bucket-wheel excavators. The risk was observed from the aspect of the danger of damage and the danger of downtime. The initial information for weak points of ES is defined according to historical damage events and statistics of downtime. Expert knowledge was used for weak points grading in the model. Additional model verification was performed using similar methods, using the same input data. The innovative model, presented in the paper, shows that it is possible to correct different weights of risk indicators. The obtained results show less dispersion compared with other existing methods. Weak points with increased risk have been located, and an algorithm has been proposed for risk-based maintenance application and implementation.

Human pluripotent stem cells (hPSCs) have been reported in naive and primed states. However, the ability to generate mature cell types remains the imperative property for utility of hPSCs. Here, we reveal that the naive state enhances self-renewal while restricting lineage differentiation in vitro to neural default fate. Molecular analyses indicate expression of multiple lineage-associated transcripts in naive hPSCs that failed to predict biased functional differentiation capacity. Naive hPSCs can be converted to primed state over long-term serial passage that permits recovery of multi-germ layer differentiation. Suppression of OCT4 but not NANOG allows immediate recovery directly from naive state. To this end, we identified chemical inhibitors of OCT4 that restore naive hPSC differentiation. Our study reveals unique cell-fate restrictions in human pluripotent states and provides an approach to overcome these barriers that harness both efficient naive hPSC growth while maintaining in vitro differentiation essential for hPSC applications.

The clinical applicability of direct cell fate conversion depends on obtaining tissue from patients that is easy to harvest, store, and manipulate for reprogramming. Here, we generate induced neural progenitor cells (iNPCs) from neonatal and adult peripheral blood using single-factor OCT4 reprogramming. Unlike fibroblasts that share molecular hallmarks of neural crest, OCT4 reprogramming of blood was facilitated by SMAD+GSK-3 inhibition to overcome restrictions on neural fate conversion. Blood-derived (BD) iNPCs differentiate in vivo and respond to guided differentiation in vitro, producing glia (astrocytes and oligodendrocytes) and multiple neuronal subtypes, including dopaminergic (CNS related) and nociceptive neurons (peripheral nervous system [PNS]). Furthermore, nociceptive neurons phenocopy chemotherapy-induced neurotoxicity in a system suitable for high-throughput drug screening. Our findings provide an easily accessible approach for generating human NPCs that harbor extensive developmental potential, enabling the study of clinically relevant neural diseases directly from patient cohorts.

Availability is one of the most used terms in maintainability engineering. This concept is used to denote: The quality of service of an engineering system, i.e., machines, weak points’ analysis, asset management, as well as making decisions in the process of life cycle management. Availability is an overall indicator and contains partial indicators that are oriented towards reliability, maintenance, and logistical support. Availability presents a variable value and changes in time and space. Usually, availability is shown as the coefficient of time use of the machine. This approach is not good enough because it does not go into the structure of the availability itself and requires a high level of IT support in system monitoring. In this sense, this paper will use the fuzzy theory and the corresponding analytic hierarchy process (AHP) multi-criteria analysis to present a conceptual and mathematical model for the assessment of availability based on expert judgment. The model will be shown in the case study (on the example) of bulldozers working in the open-pit lignite mine.