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Advances in upstream production of biologics–particularly intensified fed‐batch processes beyond 10% cell solids–have severely strained harvest operations, especially depth filtration. Bioreactors containing high amounts of cell debris (more than 40% particles <10 µm in diameter) are increasingly common and drive the need for more robust depth filtration processes, while accelerated timelines emphasize the need for predictive tools to accelerate development. Both needs are constrained by the current limited mechanistic understanding of the harvest filter‐feedstream system. Historically, process development relied on screening scale‐down depth filter devices and conditions to define throughput before fouling, indicated by increasing differential pressure and/or particle breakthrough (measured via turbidity). This approach is straightforward, but resource‐intensive, and its results are inherently limited by the variability of the feedstream. Semi‐empirical models have been developed from first principles to describe various mechanisms of filter fouling, that is, pore constriction, pore blocking, and/or surface deposit. Fitting these models to experimental data can assist in identifying the dominant fouling mechanism. Still, this approach sees limited application to guide process development, as it is descriptive, not predictive. To address this gap, we developed a hybrid modeling approach. Leveraging historical bench scale filtration process data, we built a partial least squares regression model to predict particle breakthrough from filter and feedstream attributes, and leveraged the model to demonstrate prediction of filter performance a priori. The fouling models are used to interpret and provide physical meaning to these computational models. This hybrid approach–combining the mechanistic insights of fouling models and the predictive capability of computational models–was used to establish a robust platform strategy for depth filtration of Chinese hamster ovary cell cultures. As new data continues to teach the computational models, in silico tools will become an essential part of harvest process development by enabling prospective experimental design, reducing total experimental load, and accelerating development under strict timelines. [ABSTRACT FROM AUTHOR]

In this article, the tracking control problem is addressed for uncertain nonlinear systems with actuator saturation and unmeasurable unmodeled dynamics. Being different from the existing performance function control results, to constraint the output tracking error within a predefined boundary in finite time, an improved performance function, that is, finite‐time performance function, is introduced. The design difficulties of asymmetric input saturation and unmodeled dynamics are solved simultaneously for the first time by applying a smooth non‐affine function and a measurable dynamic signal. Furthermore, an adaptive fuzzy control scheme is established via command filtering, which not only guarantees the semi‐global boundedness of all the controlled system signals but also makes the output tracking error that can be restrained by the described performance bound within a finite‐time interval. At last, an effective example is supplied to validate the availability of the presented theoretical finding. [ABSTRACT FROM AUTHOR]

In this paper, an adaptive fault‐tolerant fixed‐time control problem is considered via command‐filter technique for stochastic nonlinear systems with sensor fault and actuator hysteresis. With the application of command‐filtering technique, a novel command‐filter compensate mechanism is designed, which implies that the improved control scheme not only eliminates "the explosion of complexity" but also realizes the compensate signal is bounded within fixed‐time interval. The unavailability of state variables caused by sensor fault is solved by applying parameter separation and regrouping approach. Meanwhile, an adaptive auxiliary signal is designed to cope with the backlash‐like hysteresis phenomenon, which can avoid singularity, reduce chattering, and facilitate controller design. Combining backstepping technique and Lyapunov stability theorem, an adaptive fault‐tolerant control approach is developed, which can guarantee all closed‐loop signals remain semi‐globally practical fixed‐time stable (SGPFS) in probability. The validity of the proposed strategy is illustrated by simulation examples. [ABSTRACT FROM AUTHOR]

Aims: Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) have off‐target effects on haemoconcentration and anti‐inflammation. The impact of SGLT‐2i on the risk of venous thromboembolism (VTE) in patients with diabetes mellitus (DM) remains unclear. This study aimed to evaluate the risk of newly diagnosed VTE in patients with DM using SGLT‐2i in comparison to dipeptidyl peptidase‐4 inhibitors (DPP‐4i) or glucagon‐like peptide‐1 receptor agonists (GLP‐1RA). Materials and Methods: In this nationwide retrospective cohort study, we used data from Taiwan's National Health Insurance Research Database. Patients with diabetes aged 20 years or older who received SGLT‐2i, DPP‐4i, or GLP‐1RA between 1 May 2016, and 31 December 2020, were included. The risks of VTE in SGLT‐2i users were compared with those of DPP‐4i and GLP‐1RA users. A Cox regression model with stabilised inverse probability of treatment weighting was used to calculate hazard ratio (HR) for VTE risk. Additionally, a meta‐analysis of relevant articles published before 23 May 2023, was conducted. Results: Data from 136,530 SGLT‐2i, 598,280 DPP‐4i, and 5760 GLP‐1RA users were analysed. SGLT‐2i use was associated with a lower risk of VTE than DPP‐4i (HR, 0.70; 95% CI, 0.59–0.84; p < 0·001), but not with GLP‐1RA (HR, 1.39; 95% CI, 0.32–5.94; p = 0.66). Our meta‐analysis further supported these findings (SGLT‐2i vs. DPP‐4i: HR, 0.71; 95% CI, 0.62–0.82; p < 0·001; SGLT‐2i vs. GLP‐1RA: HR, 0.91; 95% CI, 0.73–1.15; p = 0.43), suggesting the robustness of our retrospective analysis. Conclusions: In patients with DM, SGLT‐2i was associated with a lower risk of VTE compared to DPP‐4i, but not GLP‐1RA. [ABSTRACT FROM AUTHOR]

In this article, under the circumstance of dead zones input and unknown control direction, the adaptive practical fixed‐time control strategy is presented for a general class of multi‐input and multi‐output (MIMO) nonlinear systems. The inherent explosion of computational complexity difficulty is eliminated by adopting a command filter technique and the universal approximation properties of radial basis function neural networks (RBFNNs) are applied to model the unknown nonlinear functions. The difficulties of the dynamic surface method and unknown directions can be handled by invoking error compensation mechanism and Nussbaum‐type functions, respectively. The uniqueness of the presented control scheme is that the tracking system can achieve the fixed‐time stability without relying on the boundedness of dead‐zone parameters. The fixed‐time convergence of the output tracking error and the semiglobally fixed‐time stable of closed‐loop system are assured via the developed adaptive fixed‐time command filtered controller. Finally, a practical example is supplied to further validate the availability of the presented theoretic result. [ABSTRACT FROM AUTHOR]

The problem of exponential stability for time‐delay systems with flexible delayed impulse control is investigated. Unlike the conventional Razumikhin‐type inequality, variable parameter δ(t)$$ \delta (t) $$ based on the flexible impulsive gain is introduced. Sufficient conditions for exponential stability are developed for a class of time‐delay systems, for which the size of delay is not limited by impulsive intervals. A flexible impulse control scheme is developed by utilizing the flexible impulsive gain and time‐varying delays. When the system is disturbed by the impulse interferences, both the impulse gain and impulse delay can be adjusted accordingly to make the system exponential stable. The effectiveness of the present results is illustrated by two numerical examples and an application. [ABSTRACT FROM AUTHOR]

During the course of biopharmaceutical production, heterologous protein expression in Chinese hamster ovary (CHO) cells imposes a high proteostatic burden that requires cellular adaptation. To mitigate such burden, cells utilize the unfolded protein response (UPR), which increases endoplasmic reticulum (ER) capacity to accommodate elevated rates of protein synthesis and folding. In this study, we show that during production the UPR regulates growth factor signaling to modulate growth and protein synthesis. Specifically, the protein kinase R‐like ER kinase (PERK) branch of the UPR is responsible for transcriptional down‐regulation of platelet‐derived growth factor receptor alpha (PDGFRa) and attenuation of the IRE1‐alpha (IRE1a) branch of the UPR. PERK knockout (KO) cell lines displayed reduced growth and viability due to higher rates of apoptosis despite having stabilized PDGFRa levels. Knocking out PERK in an apoptosis impaired (Bax/Bak double KO) antibody‐expressing cell line prevented apoptotic cell death and revealed that apoptosis was likely triggered by increased ER stress and reactive oxygen species levels in the PERK KO hosts. Our findings suggest that attenuation of IRE1a and PDGFRa signaling by the PERK branch of the UPR reduces ER protein folding capacity and hence specific productivity of CHO cells in order to mitigate UPR and prevent apoptotic cell death. Last, Bax/Bak/PERK triple KO CHO cell lines displayed 2–3 folds higher specific productivity and titer (up to 8 g/L), suggesting that modulation of PERK signaling during production processes can greatly improve specific productivity in CHO cells. [ABSTRACT FROM AUTHOR]

Keywords: andrology; guidelines; testosterone EN andrology guidelines testosterone 398 400 3 09/12/23 20231001 NES 231001 The function of the hypothalamic-pituitary-testicular (HPT) axis during all epochs of life is to regulate androgenization and maintain fertility through repeated incremental and decremental feedforward (stimulatory) and feedback (inhibitory) signaling among its neural and hormonal components.[1] Male hypogonadism is the clinical syndrome that results from failure to secrete sufficient testosterone (T) and/or produce spermatozoa of adequate quality or quantity due to the culmination of single, sequential or simultaneous pathophysiological abnormalities in the HPT axis.[[2], [4]] This definition is simple to apply when the cause of HPT axis failure is obvious (" I organic hypogonadism i ", e.g. due to pituitary tumor causing secondary hypogonadism or due to Klinefelter syndrome causing primary hypogonadism); however, many chronic illnesses can dysregulate the HPT axis, decrease T and impair fertility (" I functional hypogonadism i "). Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: endorsing organization: European Society of Endocrinology. [Extracted from the article]

In this article, the problem of adaptive fixed‐time tracking control is addressed for non‐triangular structural stochastic switching nonlinear systems. Fuzzy logic systems are used to compensate for unknown nonlinearities, and in the meantime, to avoid the algebraic loop problem, which exists in traditional backstepping controller design processes for non‐triangular structural nonlinear systems. The unknown control gain problem is addressed by the construction of proper Lyapunov function candidates. By employing Lyapunov stability theorem, all the closed‐loop signals can be ensured to be semi‐globally practical fixed‐time stable, the output signal can track the desired signal, and the tracking error can converge to a small zone around the origin. The effectiveness of the developed control approach is verified through simulation results. [ABSTRACT FROM AUTHOR]

Aims: Guidelines for the management of heart failure (HF) are evolving, and increasing emphasis is placed on patient‐centred care. As part of the REWOLUTION HF (REal WOrLd EdUcaTION in HF) programme, we conducted two international surveys aimed at assessing healthcare professionals' (HCPs) educational needs and patients' perspectives on the care of HF. Methods and results: Anonymous online questionnaires co‐developed by HF experts and patients assessed HCPs' educational needs (520 respondents, mostly cardiologists, in 67 countries) and patients' perceptions on HF impact and management (98 respondents in 18 countries). Among HCPs, 62.7% prioritized rapid initiation of all guideline‐mandated medications over up‐titration of some medications, and 87.7% always or frequently discussed treatment goals with patients. There was good agreement between HCPs and patients on key treatment goals, except for a greater emphasis on reducing hospitalizations among HCPs. The most frequently cited barriers to the provision of guideline‐recommended pharmacological therapy were treatment side effects/intolerance, complex treatment regimens, low blood pressure, cost/reimbursement issues, and low estimated glomerular filtration rate. Most patients (81.6%) reported no difficulties taking medications as prescribed, although 21.4% felt they were taking too many pills. Patients wanted more information about HF and its consequences, prognosis, and treatments (70.4%, 74.5% and 76.6%, respectively). Cardiologists were the preferred source of information about HF, followed by general practitioners and HF nurses. Conclusions: These surveys provide valuable insights into HCPs' needs about personalized care for patients with HF, as well as patients' perceptions, expectations and preferences. These findings will be helpful to develop patient‐centred, needs‐driven quality improvement programmes. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a progressive liver disease for which there is no effective therapy. Hepatocytes and cholangiocytes from a PSC patient were cocultured with mesenchymal stem cells (MSCs) to assess in vitro change. A single patient with progressive PSC was treated with 150 million MSCs via direct injection into the common bile duct. Coculture of MSCs with cholangiocytes and hepatocytes showed in vitro improvement. Local delivery of MSCs into a single patient with progressive PSC was safe. Radiographic and endoscopic evaluation showed stable distribution of multifocal structuring in the early postoperative period. MSCs may be effective for the treatment of PSC. [ABSTRACT FROM AUTHOR]

Summary: A new fault‐tolerant approach to input saturation and sensor faults is presented for flexible‐joint robotic stochastic nonlinear systems with finite‐time convergence performance. More precisely, a new command filter is designed and embedded into the backstepping framework, which greatly reduces the amount of calculation. By using the estimation ability of fuzzy logic system and less adjustable parameters, the problems of sensor faults and unknown functions are solved, which facilitates the design of controllers. A smooth function and mean‐value theorem are used to deal with the difficulty associated with system signals. A novel simpler controller is developed to ensure that the trajectory tracking error converges to a sufficiently small neighborhood around the origin within finite time, while there are random noises. Finally, the effectiveness of the presented scheme is verified by simulation results. [ABSTRACT FROM AUTHOR]

Summary: The time‐constrained positional synchronization control problem for a class of bilateral teleoperation systems is investigated and a novel fixed‐time event‐triggered control scheme is developed. Different from existing methods, the controller is triggered in a nonperiodic manner, which reduces considerably the triggering frequency of control devices. This not only saves communication resource, but also extends the lifespan of system devices because of the reduction of switching times. The control settling time is further considered by introducing a fixed‐time stability theorem. Theoretical analysis as well as a simulation example verifies that the proposed control method can reduce remarkably the amount of control signals transmitted between the master and slave while ensuring that the system output tracking error converges to a small neighborhood close to zero within a fixed‐time frame. [ABSTRACT FROM AUTHOR]

Summary: This article copes with the adaptive fixed‐time funnel control problem for a class of nonlinear systems with actuator faults. To deal with the difficulties due to actuator faults, which include both lock‐in‐place and loss‐of‐effectiveness models, an adaptive fault‐tolerant control scheme is proposed. By introducing the fuzzy logic system and backstepping technique, an adaptive fixed‐time controller is developed to ensure that the tracking error converges into a pre‐specified performance funnel within a fixed time, which is independent on the initial state, and in the meantime, the controlled closed‐loop system remains semi‐global fixed‐time bounded stable and all the signals are bounded. Simulation results verify the proposed approach. [ABSTRACT FROM AUTHOR]

Myocarditis and pericarditis may constitute adverse reactions of mRNA coronavirus disease 2019 (COVID‐19) vaccines. This study aimed to document these reactions and to assess the association with patient sex and age. This is as an observational retrospective study using a case–non‐case design (also called disproportionality study) on inflammatory heart reactions reported with mRNA COVID‐19 vaccines within the World Health Organization (WHO) global safety database (VigiBase), up to June 30, 2021. Results are expressed using reporting odds ratios (RORs) and their 95% confidence interval (95% CI). Of 716,576 reports related to mRNA COVID‐19 vaccines, 2,277 were cases of inflammatory heart reactions, including 1241 (55%) myocarditis and 851 (37%) pericarditis. The main age group was 18–29 years (704, 31%), and mostly male patients (1,555, 68%). Pericarditis onset was delayed compared with myocarditis with a median time to onset of 8 (3–21) vs. 3 (2–6) days, respectively (P = 0.001). Regarding myocarditis, an important disproportionate reporting was observed in adolescents (ROR, 22.3, 95% CI 19.2–25.9) and in 18–29 years old (ROR, 6.6, 95% CI 5.9–7.5) compared with older patients, as well as in male patients (ROR, 9.4, 95% CI 8.3–10.6). Reporting rate of myocarditis was increased in young adults and adolescents. Inflammatory heart reactions may rarely occur shortly following mRNA COVID‐19 vaccination. Although an important disproportionate reporting of myocarditis was observed among adolescents and young adults, particularly in male patients, reporting rates support a very rare risk, that does not seem to compromise the largely positive benefit‐risk balance of these vaccines. Furthermore, this study confirmed the value of disproportionality analyses for estimation of relative risks among subgroups of patients. [ABSTRACT FROM AUTHOR]

Existing techniques for optical trapping and manipulation of microscopic objects, such as optical tweezers and plasmonic tweezers, are mostly based on visible and near‐infrared light sources. As it is in general more difficult to confine light to a specific length scale at a longer wavelength, these optical trapping and manipulation techniques have not been extended to the mid‐infrared spectral region or beyond. Here, it is shown that by taking advantage of the fact that many materials have large permittivity dispersions in the mid‐infrared region, optical trapping and manipulation using mid‐infrared excitation can achieve additional functionalities and benefits compared to the existing techniques in the visible and near‐infrared regions. In particular, it is demonstrated that by exploiting the exceedingly high field confinement and large frequency tunability of mid‐infrared graphene plasmonics, high‐performance and versatile mid‐infrared plasmonic tweezers can be realized to selectively trap or repel nanoscale objects of different materials in a dynamically reconfigurable way. This new technique can be utilized for sorting, filtering, and fractionating nanoscale objects in a mixture. [ABSTRACT FROM AUTHOR]

Summary: This article focuses on the finite‐time adaptive fuzzy control problem based on command filtering for stochastic nonlinear systems subject to input quantization. Fuzzy logic systems are employed to estimate unknown nonlinearities. In the control design, the hysteretic quantized input is decomposed into two bounded nonlinear functions, which solves the chattering problem. Meanwhile, an adaptive fuzzy controller is presented by the combination of command filter technique and backstepping control, which eliminates the computational complexity existing in traditional backstepping design. Under the proposed adaptive mechanism, all the closed‐loop signals remain bounded while the desired system performance can be realized within finite time. The main significance of this work is that (1) the filtering error can be solved on the basis of the designed compensating signals; (2) the requirement of adaptive parameters is decreased to only one, which simplifies the controller design process and may improve the control performance. Two simulation examples are used to validity of the developed scheme. [ABSTRACT FROM AUTHOR]

Short‐term load forecasting is essential to power systems management. However, most existing forecasting methods fail to fully consider how to rationally integrate the intrinsic time‐related dimensions of electric load data and the decomposition methods into machine learning models so that their prediction accuracy and robustness still have much room for improvement. To solve this problem, this paper proposes a decomposition‐based multi‐time dimension long short‐term memory (DB‐MTD‐LSTM) model for short‐term electric load forecasting (STELF). In DB‐MTD‐LSTM, empirical mode decomposition with adaptive noise (CEEMDAN) is first introduced to smooth non‐linear non‐stationary electric load data and constrain the modal aliasing or noise of decomposed electric load data in the traditional decomposed method. A joint relevant time dimensions method (JRTDM) is then developed using autocorrelation analysis to rationally extract the temporal characteristics of decomposed data in multiple time dimensions. An improved LSTM called MTD‐LSTM is developed by combining JRTDM with LSTM, which can effectively apply multi‐dimensional time characteristics of the decomposed load to improve the predictive accuracy and robustness. Several datasets from Australia and China are performed to check the predictive performance of DB‐MTD‐LSTM. Experimental results verify that DB‐MTD‐LSTM has better predictive accuracy and satisfactory robustness compared with state‐of‐the‐art and conventional predictive models. [ABSTRACT FROM AUTHOR]

A second‐order adaptive integral terminal sliding mode controller is proposed for the trajectory tracking control of robotic manipulators with uncertainties. A second‐order integral terminal sliding mode surface is designed for which an integral sliding mode (ISM) surface and a fast nonsingular integral terminal sliding mode surface are combined. By using the ISM surface, the reaching phase is removed, which enhances system robustness. The steady‐state error is reduced because of the presence of an error integral term. A fast second‐order nonsingular integral terminal sliding mode surface is employed to ensure that the ISM surface is able to converge to zero rapidly within a finite period of time without leading to a singularity problem. The control input of the proposed controller is continuous. Thus, the chattering phenomenon is removed. An adaptation technique is employed to estimate the upper bound of unknown lumped disturbance. The second‐order derivative of position is calculated using a robust differentiator, making it practical. Simulations and experiments show that the proposed scheme improves the tracking performance and eliminates chattering. [ABSTRACT FROM AUTHOR]

Summary: An adaptive finite‐time decentralized control algorithm for a class of large‐scale stochastic nonlinear systems is presented. The fuzzy logic system is used to estimate uncertain nonlinearities. One advantage of the developed scheme is that each subsystem only needs to update one adaptive parameter, which alleviates the burden of online estimation. The dynamic surface control method is employed to reduce the "complexity explosion" caused by the repetitive derivation of the intermediate variable function in the backstepping control scheme. A new decentralized controller is designed so that all signals of the controlled system are bounded and the tracking error converges to a small residual set around the origin within a finite time. The simulation results of a numerical example illustrate the effectiveness of the method. [ABSTRACT FROM AUTHOR]

Deletion of the pyruvate kinase muscle (PKM) gene, which is involved in conversion of phosphoenolpyruvate to pyruvate, has been shown to curb lactogenic behavior in Chinese hamster ovary (CHO) cells. This study describes the generation of pyruvate kinase muscle isoforms 1 and 2 knockout (PKM‐KO) and pyruvate kinase muscle isoform‐1 knockout (PKM1‐KO) CHO host cells to understand metabolic shifts that reduce lactate secretion in these cells. Glucose and amino acids uptake levels in wild‐type (WT), PKM‐KO, and PKM1‐KO stable cell lines, expressing two different antibodies, were analyzed in 14‐day fed‐batch production assays using different vessels. PKM‐KO and PKM1‐KO cells consumed more glucose per cell, altered amino acids metabolism, had higher flux of pyruvate into the tricarboxylic acid (TCA) cycle, and as previously shown reduced lactate secretion levels compared with the WT cells. Additionally, both PKM‐KO and PKM1‐KO cells had higher specific productivity and lower cell growth rates compared with the WT cells. Our findings suggest that rewiring the flux of pyruvate to the TCA cycle by deletion of PKM or PKM1 reduced cell growth and increased specific productivity in CHO cells. Overall, PKM1‐KO cells had similar product quality and comparable or better titers relative to the WT cells, hence, targeted deletion of this isoform for curbing lactogenic behavior in CHO cells is suggested. [ABSTRACT FROM AUTHOR]

Background: Dimethandrolone (DMA) and 11β‐methyl‐19‐nortestosterone (11β‐MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. Objective: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. Materials/Methods: In two clinical trials of DMA undecanoate (DMAU) and 11β‐MNT dodecylcarbonate (11β‐MNTDC), oral prodrugs of DMA and 11β‐MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non‐parametric Kruskal‐Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. Results: Class effects were seen, with decrease in HDL‐C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA‐IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11β‐MNTDC. An increase in LDL‐C was seen with 11β‐MNTDC but not with DMAU. Discussion: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. Conclusion: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds. [ABSTRACT FROM AUTHOR]

The adaptive neural tracking fault‐tolerant control problem is considered for nonlinear non‐affine switched systems with sensor faults via dynamic surface control (DSC) technique under arbitrary switchings within predefined‐time interval. During the controller design process, the non‐affine formation strictly processed so that the implicit control signals can be transformed into explicit ones. The introduction of hyperbolic tangent function to design the control signal eliminates the singularity at the same time, but also avoids the tedious discussion of the segmentation function to solve the singularity. Considering Lyapunov stability theorem, an adaptive fault tolerant control approach is presented, which means that the settling‐time can be programmed by the user practical specification under arbitrary switching, the predefined time boundedness of all closed‐loop signals can be ensured, and the influence of sensor faults can be compensated. The effectiveness of the presented method is verified via simulation results. [ABSTRACT FROM AUTHOR]

Summary: This article investigates the problem of event‐trigger based adaptive backstepping control for a class of nonlinear fractional order systems. By introducing an appropriate transformation of frequency distributed model, the fractional‐order indirect Lyapunov method with 0<β<1 is obtained. In addition, the event‐triggered adaptive controller is developed by employing the event‐triggered control approach. Meanwhile, by the proposed adaptive control scheme, all the closed‐loop signals are globally uniformly bounded, and the tracking error converges to a small neighborhood of the origin. Finally, simulation results are provided to testify the availability of the presented controller. [ABSTRACT FROM AUTHOR]

Aim: To compare the risk of diabetes development in patients with atrial fibrillation (AF) treated with non‐vitamin K antagonist oral anticoagulants (NOACs) and warfarin. Materials and Methods: We conducted a nationwide retrospective cohort study using Taiwan's National Health Insurance Research Database. Adult patients with new onset of AF, treated with NOACs or warfarin between 2012 and 2016, were included. The NOAC cohort was further divided into dabigatran, rivaroxaban and apixaban groups. The primary outcome was incident diabetes requiring treatment with antidiabetic drugs. Fine and Gray subdistribution hazards models were used to estimate the adjusted hazard ratio (aHR). Propensity score matching was performed for each head‐to‐head comparison. Results: A total of 10 746 new‐onset AF patients were included in our study. During the mean 2.4‐year follow‐up, NOACs were associated with a lower risk of developing diabetes than warfarin (aHR = 0.80, 95% confidence interval [CI]: 0.68‐0.94, P =.007). Subgroup analyses confirmed that dabigatran, rivaroxaban and apixaban each had a reduced diabetes risk. Stratified analyses showed that the lower risk of diabetes associated with NOAC treatment was specific to patients aged 65 years or older (aHR = 0.74, 95% CI: 0.62‐0.89, P =.002) and those with good medication adherence (aHR = 0.70, 95% CI: 0.58‐0.84, P <.001). Conclusions: Taking an NOAC was associated with a lower risk of developing diabetes than taking warfarin in patients with AF. [ABSTRACT FROM AUTHOR]

In this study, an adaptive fractional‐order non‐singular fast terminal sliding mode (FO‐NFTSM) scheme based on time delay estimation (TDE) is proposed for the control of robotic manipulators. A new FO‐NFTSM surface with a continuous TSM‐type switch item is designed to ensure good performance, such as fast finite‐time convergence, high precision and being non‐singular. The chattering problem is solved by introducing a saturation function into the control signal. The TDE element is used to estimate the robot's unknown dynamic parameters and external disturbances. The Lyapunov stability theory is used to prove the finite‐time stability of the control system. The proposed control algorithm is applied to a two‐link robotic manipulator and the comparative results verify the effectiveness and superiority of the proposed control approach in comparison with existing control methods. [ABSTRACT FROM AUTHOR]

Chinese hamster ovary (CHO) cells have been adapted to grow in serum‐free media and in suspension culture to facilitate manufacturing needs. Some CHO cell lines, however, tend to form cell aggregates while being cultured in suspension. This can result in reduced viability and capacity for single cell cloning (SCC) via limiting dilution, and process steps to mitigate cell aggregate formation, for example, addition of anti‐cell‐aggregation agents. In this study, we have identified endothelial intercellular cell adhesion molecule 1 (ICAM‐1) as a key protein promoting cell aggregate formation in a production competent CHO cell line, which is prone to cell aggregate formation. Knocking out (KO) the ICAM‐1 gene significantly decreased cell aggregate formation in the culture media without anti‐cell‐aggregation reagent. This trait can simplify the process of transfection, selection, automated clone isolation, and so on. Evaluation in standard cell line development of ICAM‐1 KO and wild‐type CHO hosts did not reveal any noticeable impacts on titer or product quality. Furthermore, analysis of a derived nonaggregating cell line showed significant reductions in expression of cell adhesion proteins. Overall, our data suggest that deletion of ICAM‐1 and perhaps other cell adhesion proteins can reduce cell aggregate formation and improve clonality assurance during SCC. [ABSTRACT FROM AUTHOR]

Summary: The finite‐time tracking control problem with the output‐constraint property of robotic manipulators subjected to system uncertainties is addressed. Specifically, the radial basis function neural network is employed to compensate for system uncertainties. The finite‐time stability theorem is used for the backstepping design process, by which the limit of the settling time is set. A funnel boundary is used to limit the output overshoot. The proposed controller guarantees that all the signals are semi‐globally practically finite‐time bounded, while the tracking errors are enveloped by the funnel boundary. The performance of the proposed control method is illustrated by a numerical simulation of a 3‐DOF manipulator. It is shown that the tracking errors are bounded by prescribed funnel boundaries. In the meantime, the manipulator is stabilized within a finite period of time. [ABSTRACT FROM AUTHOR]

Background: Focal impulse and rotor modulation (FIRM) can cause slowing, organization, and occasionally termination of atrial fibrillation (AF), although results have been mixed. To further characterize changes in AF during rotor ablation, we quantified morphologic and temporal activation changes following FIRM. Methods: In patients undergoing FIRM ablation for AF, we retrospectively analyzed coronary sinus bipolar EGMs before and after rotor ablation, including EGM activation frequency and regularity, dominant frequency (DF), and organizational index (OI). Changes in EGM waveform morphology were determined with recurrence quantification analysis (RQA) consisting of recurrence rate (RR), determinism (DET), laminarity (LAM), average diagonal line length (L), and trapping time (TT) using Wilcoxon signed‐rank testing. Results: Overall, 36 rotors from 21 patients undergoing FIRM ablation were analyzed. All morphology RQA parameters demonstrated significant organization of atrial activation after rotor ablation (RR P =.03, DET P =.005, LAM P =.03, L P =.005, TT P =.009). The organizational index also showed a significant increase after rotor ablation (P =.01), and the change in OI correlated with changes in all morphology parameters. Of the rotors, 14/36 (39%) rotors showed organizational changes in all morphology parameters and OI, and an additional 5 rotors (19/36, 53%) showed organizational changes in 4 of 5 morphology parameters and OI. Conclusions: Coronary sinus EGM waveform morphologies and activation patterns are significantly altered after FIRM ablation even when there is no fibrillatory slowing. RQA morphology analysis and organizational index may impart important information regarding underlying AF organization and may be useful in quantifying the acute response to ablation. [ABSTRACT FROM AUTHOR]

Background: Breast cancer therapies are associated with a risk of cardiac dysfunction, most commonly defined by changes in left ventricular ejection fraction (LVEF). Recently, the authors identified 3 classes of LVEF change after exposure to anthracyclines and/or trastuzumab using latent class growth modeling. The objective of the current study was to characterize the clinical, biochemical, and functional profiles associated with LVEF trajectory class membership. Methods: Transthoracic echocardiography and biomarker assessments were performed and questionnaires were administered at standardized intervals in a longitudinal cohort of 314 patients with breast cancer who were treated with anthracyclines and/or trastuzumab. Univariable and multivariable multinomial regression analyses evaluated associations between baseline variables and LVEF trajectory class membership. Generalized estimating equations were used to define mean changes in cardiovascular measures over time within each class. Results: Among the 3 distinct subgroups of LVEF changes identified (stable [class 1]; modest, persistent decline [class 2]; and significant early decline followed by partial recovery [class 3]), higher baseline LVEF, radiotherapy, and sequential therapy with anthracyclines and/or trastuzumab were associated with class 2 or 3 membership. Sustained abnormalities in longitudinal strain and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were observed in patients in class 2, as were heart failure symptoms. Similar abnormalities were observed in patients in class 3, but there was a trend toward recovery, particularly for longitudinal strain. Conclusions: Patients with modest, persistent LVEF declines experienced sustained abnormalities in imaging and biochemical markers of cardiac function and heart failure symptoms. Further investigation is needed to characterize the long‐term risk of heart failure, particularly in those with modest LVEF declines. Modest declines in left ventricular ejection fraction (LVEF) in patients with breast cancer who are treated with cardiotoxic cancer therapy are accompanied by an increased incidence of biochemical and functional abnormalities. This suggests that declines in LVEF that do not reach the conventional thresholds used for the diagnosis of cardiotoxicity could be more clinically important than previously understood. [ABSTRACT FROM AUTHOR]

Hypertension, the leading cause of cardiovascular morbidity and mortality, affects more than 1 billion people globally. The rise in mobile health in particular the use of mobile phones and short message service (SMS) to support disease management provides an opportunity to improve hypertension awareness, treatment, and control, in remote and vulnerable patient populations. The primary objective of this randomized controlled study was to assess the effect of active (with hypertension specific management SMS) or passive (health behaviors SMS alone) on the difference in blood pressure (BP) reduction between the active and passive SMS groups in hypertensive Canadian First Nations people from six rural and remote communities. Pragmatic features of the study included shifting of BP measures to non-medical health workers. Despite an overall reduction in BP over the study, there was no difference in the BP change between groups from baseline to final for systolic 0.8 (95% CI -4.2 to 5.8 mm Hg) or diastolic -1.0 (95% CI -3.7 to 1.8 mm Hg, P = 0.5) BP. Achieved BP control was 37.5% (25.6%-49.4%, 95% CI) in the active group and 32.8% (20.6%-44.8%, 95% CI) in the passive group (difference in proportions -4.74% (-21.7% to 12.2%, 95% CI, P = 0.6). The study looked at changes in health services delivery, mobile health technologies, and patient engagement to support better management of hypertension in Canadian First Nations communities. The active hypertension specific SMS did not lead to improvements in BP control. [ABSTRACT FROM AUTHOR]

Summary: The aim was to investigate whether continuous positive airway pressure treatment could modulate serum vitamin D (25‐hydroxyvitamin D) and bone turnover markers (collagen‐type 1 cross‐linked C‐telopeptide, osteocalcin and N‐terminal propeptide of type 1 collagen) in secondary analysis from a randomized controlled trial. Sixty‐five continuous positive airway pressure‐naïve male patients with obstructive sleep apnea (age = 49 ± 12 years, apnea–hypopnea index = 39.9 ± 17.7 events h−1, body mass index = 31.3 ± 5.2 kg m−2) were randomized to receive either real (n = 34) or sham (n = 31) continuous positive airway pressure for 12 weeks. At 12 weeks, all participants received real continuous positive airway pressure for an additional 12 weeks. After 12 weeks of continuous positive airway pressure (real versus sham), there were no between‐group differences for any of the main outcomes [Δ25‐hydroxyvitamin D: −0.80 ± 5.28 ng mL−1 (mean ± SE) versus 3.08 ± 3.66 ng mL−1, P = 0.42; Δcollagen‐type 1 cross‐linked C‐telopeptide: 0.011 ± 0.014 ng mL−1 versus −0.004 ± 0.009 ng mL−1, P = 0.48; Δosteocalcin: 1.13 ± 1.12 ng mL−1 versus 0.46 ± 0.75 ng mL−1, P = 0.80; ΔN‐terminal propeptide of type 1 collagen: 2.07 ± 3.05 μg L−1 versus −1.05 ± 2.13 μg L−1, P = 0.48]. There were no further differences in subgroup analyses (continuous positive airway pressure‐compliant patients, patients with severe obstructive sleep apnea or sleepy patients). However, after 24 weeks irrespective of initial randomization, vitamin D increased in patients with severe obstructive sleep apnea (9.56 ± 5.51 ng mL−1, P = 0.045) and in sleepy patients (14.0 ± 4.69 ng mL−1, P = 0.007). Also, there was a significant increase in osteocalcin at 24 weeks (3.27 ± 1.06 ng mL−1, P = 0.01) in compliant patients. We conclude that 12 weeks of continuous positive airway pressure did not modulate vitamin D or modulate any of the bone turnover markers compared with sham. However, it is plausible that continuous positive airway pressure may have late beneficial effects on vitamin D levels and bone turnover markers in selected groups of patients with obstructive sleep apnea. [ABSTRACT FROM AUTHOR]

During expression of biotherapeutic proteins, complex mixtures of additional proteins are also produced by normal expression machinery of the host cell (termed 'host cell proteins,' or HCP). HCPs pose a potential impact to patient safety and product efficacy, and therefore must be well-characterized and the ability of the process to clear these proteins must be demonstrated. Due to the complexity of HCP, the method(s) used for monitoring must be demonstrated to provide sufficient information about relevant proteins. The most commonly used analytical method for monitoring HCP is an enzyme-linked immunosorbent assay (ELISA). To ensure development of a suitable HCP ELISA, careful selection of critical reagents (anti-HCP antibodies and analytical standard) is crucial. During a recent major update to the manufacturing process of a biotherapeutic, we re-evaluated the suitability of the existing HCP ELISA for monitoring the HCP population in the updated process. In the evaluation, we compared a process-specific ELISA to a platform ELISA. Despite qualitative differences in the HCP profiles in 2D PAGE, LC-MS/MS showed that the HCP populations in the two analytical standards were similar. The process-specific HCP antibody had adequate HCP coverage, but was more sensitive to a few dominant proteins that were present in the upstream purification process. The platform HCP antibody had very broad coverage and additionally, could detect the majority of potential HCP impurities from this process. Furthermore, the platform HCP antibody was not biased toward a few dominant proteins and was more sensitive in the downstream purification process. Due to its broad HCP coverage and sensitivity, we conclude that our platform HCP ELISA method is superior to the process-specific HCP ELISA method. [ABSTRACT FROM AUTHOR]

ISWI chromatin remodelers mobilize nucleosomes to control DNA accessibility. Complexes isolated to date pair one of six regulatory subunits with one of two highly similar ATPases. However, we find that each endogenously expressed ATPase co-purifies with every regulatory subunit, substantially increasing the diversity of ISWI complexes, and we additionally identify BAZ2B as a novel, seventh regulatory subunit. Through reconstitution of catalytically active human ISWI complexes, we demonstrate that the new interactions described here are stable and direct. Finally, we profile the nucleosome remodeling functions of the now expanded family of ISWI chromatin remodelers. By revealing the combinatorial nature of ISWI complexes, we provide a basis for better understanding ISWI function in normal settings and disease. [ABSTRACT FROM AUTHOR]

Due to the increasing integration of photovoltaic‐based distributed generators (PV‐DGs), uncertainties resulted from both PV‐DG power and loads have posed a serious challenge in microgrid day‐ahead scheduling and operation. In this study, the effect of uncertainties in both PV‐DG power and loads on the microgrid day‐ahead scheduling is assessed. Specifically, the correlation between the PV‐DG power and load uncertainties is taken into account as this is closer to the reality. The probabilistic optimal power flow (P‐OPF) model is formulated to analyse the impact of the correlated PV‐DG power and load uncertainties. A modified Harr's two‐point estimation method (MH‐2PEM) is introduced to provide computation‐efficient estimation of the P‐OPF solution. Results obtained by using the MH‐2PEM and Monte Carlo simulation are compared in an equivalent 44 kV distribution feeder system and the accuracy and efficiency of the MH‐2PEM are verified. The variation ranges of the microgrid day‐ahead scheduling solution resulted from uncertainties in PV power and load are obtained with various confidence levels. [ABSTRACT FROM AUTHOR]

Objective Acutely restricting sleep worsens insulin sensitivity in healthy individuals whose usual sleep is normal in duration and pattern. The effect of recovery or weekend 'catch-up' sleep on insulin sensitivity and metabolically active hormones in individuals with chronic sleep restriction who regularly 'catch-up' on sleep at weekends is as yet unstudied. Design 19 men (mean ± SEM age 28·6 ± 2·0 years, BMI 26·0 ± 0·8 kg/m2) with at least 6 months' history (5·1 ± 0·9 years) of lifestyle-driven, restricted sleep during the working week (373 ± 6·6 min/night) with regular weekend 'catch-up' sleep (weekend sleep extension 37·4 ± 2·3%) completed an in-laboratory, randomized, crossover study comprising two of three conditions, stratified by age. Conditions were 3 weekend nights of 10 hours, 6 hours or 10 hours time-in-bed with slow wave sleep (SWS) suppression using targeted acoustic stimuli. Measurements Insulin sensitivity was measured in the morning following the 3rd intervention night by minimal modelling of 19 samples collected during a 2-h oral glucose tolerance test. Glucose, insulin, c-peptide, leptin, peptide YY (PYY), ghrelin, cortisol, testosterone and luteinizing hormone ( LH) were measured from daily fasting blood samples; HOMA- IR, HOMA-β and QUICKI were calculated. Results Insulin sensitivity was higher following three nights of sleep extension compared to sustained sleep restriction. Fasting insulin, c-peptide, HOMA- IR, HOMA-β, leptin and PYY decreased with 'catch-up' sleep, QUICKI and testosterone increased, while morning cortisol and LH did not change. Targeted acoustic stimuli reduced SWS by 23%, but did not alter insulin sensitivity. Conclusions Three nights of 'catch-up' sleep improved insulin sensitivity in men with chronic, repetitive sleep restriction. Methods to improve metabolic health by optimizing sleep are plausible. [ABSTRACT FROM AUTHOR]

ABSTRACT Host cell proteins (HCPs) are among the process-related impurities monitored during recombinant protein pharmaceutical process development. The challenges of HCP detection include (1) low levels of residual HCPs present in large excess of product protein, (2) the assay must measure a large number of different protein analytes, and (3) the population of HCP species may change during process development. Suitable methods for measuring process-related impurities are needed to support process development, process validation, and control system testing. A multi-analyte enzyme-linked immunosorbent assay (ELISA) is the workhorse method for HCP testing due to its high throughput, sensitivity and selectivity. However, as the anti-HCP antibodies, the critical reagents for HCP ELISA, do not comprehensively recognize all the HCP species, it is especially important to ensure that weak and non-immunoreactive HCPs are not overlooked by the ELISA. In some cases limited amount of antibodies to HCP species or antigen excess causes dilution-dependent non-linearity with multi-product HCP ELISA. In our experience, correct interpretation of assay data can lead to isolation and identification of co-purifying HCP with the product in some cases. Moreover, even if the antibodies for a particular HCP are present in the reagent, the corresponding HCP may not be readily detected in the ELISA due to antibody/antigen binding conditions and availability of HCP epitopes. This report reviews the use of the HCP ELISA, discusses its limitations, and demonstrates the importance of orthogonal methods, including mass spectrometry, to complement the platform HCP ELISA for support of process development. In addition, risk and impact assessment for low-level HCPs is also outlined, with consideration of clinical information. Biotechnol. Bioeng. 2014;111: 2367-2379. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: With increased use of handheld and tablet display devices for viewing medical images, methods for consistently measuring reflectivity of the devices are needed. In this note, the authors report on the characterization of diffuse reflections for handheld display devices including mobile phones and tablets using methods recommended by the American Association of Physicists in Medicine Task Group 18 (TG18). Methods: The authors modified the diffuse reflectance coefficient measurement method outlined in the TG18 report. The authors measured seven handheld display devices (two phones and five tablets) and three workstation displays. The device was attached to a black panel with Velcro. To study the effect of the back surface on the diffuse reflectance coefficient, the authors created Styrofoam masks with different size square openings and placed it in front of the device. Overall, for each display device, measurements of illuminance and reflected luminance on the display screen were taken. The authors measured with no mask, with masks of varying size, and with display-size masks, and calculated the corresponding diffuse reflectance coefficient. Results: For all handhelds, the diffuse reflectance coefficient measured with no back panel were lower than measurements performed with a mask. The authors found an overall increase in reflectivity as the size of the mask decreases. For workstations displays, diffuse reflectance coefficients were higher when no back panel was used, and higher than with masks. In all cases, as luminance increased, illuminance increased, but not at the same rate. Conclusions: Since the size of handheld displays is smaller than that of workstation devices, the TG18 method suffers from a dependency on illumination condition. The authors show that the diffuse reflection coefficients can vary depending on the nature of the back surface of the illuminating box. The variability in the diffuse coefficient can be as large as 20% depending on the size of the mask. For all measurements, both luminance and illuminance increased as the size of the display window decreased. The TG18 method does not account for this variability. The authors conclude that the method requires a definitive description of the back panel used in the light source setup. The methods described in the TG18 document may need to be improved to provide consistent comparisons of desktop monitors, phones, and tablets. [ABSTRACT FROM AUTHOR]