Endpoint Determination Research Articles

A Gaussian Process Model-Guided Surface Polishing Process in Additive Manufacturing

Abstract Polishing of additively manufactured products is a multi-stage process, and a different combination of polishing pad and process parameters is employed at each stage. Pad change decisions and endpoint determination currently rely on practitioners’ experience and subjective visual inspection of surface quality. An automated and objective decision process is more desired for delivering consistency and reducing variability. Toward that objective, a model-guided decision-making scheme is developed in this article for the polishing process of a titanium alloy workpiece. The model used is a series of Gaussian process models, each established for a polishing stage at which surface data are gathered. The series of Gaussian process models appear capable of capturing surface changes and variation over the polishing process, resulting in a decision protocol informed by the correlation characteristics over the sample surface. It is found that low correlations reveal the existence of extreme roughness that may be deemed surface defects. Making judicious use of the change pattern in surface correlation provides insights enabling timely actions. Physical polishing of titanium alloy samples and a simulation of this process are used together to demonstrate the merit of the proposed method.

Combining convolutional neural networks and in-line near-infrared spectroscopy for real-time monitoring of the chromatographic elution process in commercial production of notoginseng total saponins.

The chromatographic elution process is a key step in the production of notoginseng total saponins. Due to quality variability of loading samples and resin capacity decreasing over cycle time, saponins, especially the five main saponins of notoginseng total saponins, need to be monitored in real time during the elution process. In this study, convolutional neural networks, one of the most popular deep learning methods, were used to develop quantitative calibration models based on in-line near-infrared spectroscopy for notoginsenoside R1 , ginsenosides Rg1 , Re, Rb1 and Rd, and their sum concentration, with root mean square error of prediction values of 0.87, 2.76, 0.60, 1.57, 0.28, and 4.99mg/mL, respectively. Partial least squares calibration models were also developed for model performance comparison. Results show predicted concentration profiles outputted by both the convolutional neural network models and partial least squares models show agreements with the real trends defined by reference measurements, and can be used for elution process monitoring and endpoint determination. To the best of our knowledge, this is the first reported case study of combining convolutional neural networks and in-line near-infrared spectroscopy for monitoring of the chromatographic elution process in commercial production of botanical drug products.

A 10-MHz Hysteretic-Controlled Buck Converter With Single On/Off Reference Tracking Using Turning-Point Prediction for DVFS Application

This paper presents a turning-point output voltage (TPOV) prediction method to enhance the reference tracking speed of buck converters for dynamic voltage and frequency scaling (DVFS) application. The optimal reference tracking is modeled, and the TPOV is formulated. The parasitic effects are compensated with the proposed calibration scheme. Reference tracking considering load current changes is evaluated with the proposed end-point determination method. Additionally, this work optimizes the feedback network for smooth loop transition, and incorporates the frequency-locking circuit and the error correction path to address the shortcomings of the hysteretic control. The prototype is fabricated in a 0.13- $\mu \text{m}$ CMOS process with a 1.2-V supply voltage. The converter achieves a near-optimum reference tracking over a wide range of output voltages, from 0.5 to 1 V. Various output voltage steps are measured for different load cases. For a 0.5–1-V output voltage step, with a 90-nH inductor and a 1- $\mu \text{F}$ output capacitor, the up- and down-tracking take 558 and 542 ns, respectively, matching the theoretical result of 533 ns. The prototype achieves a peak efficiency of 93.5%, and over 85% efficiency is measured with $\mathrm {V}_{\mathrm {O}}$ from 0.5 to 1 V and $\mathrm {I}_{\mathrm {O}}$ from 130 to 550 mA.

Scientific and Regulatory Policy Committee Points to Consider*: The Toxicologic Pathologist's Role in the 3Rs.

Pathologists are trained medical professionals with special expertise in diagnostics, research, and pathophysiology. In these roles, pathologists are well qualified and positioned to engage in conversations about animal use replacement, reduction, and refinement (3Rs), thereby championing the guiding principles of the 3Rs. In particular, toxicology or nonclinical safety assessment is an important area where the discipline of toxicologic pathology can have a critical role in adopting 3Rs principles. As such, a working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee was formed to investigate and summarize some of the areas where veterinary pathologists working in the field of toxicology can increase involvement and impact on 3Rs. This "Points to Consider" publication provides an overview of areas within toxicology where the veterinary pathologist's perspective may maximize animal value, including refinement of study design, optimizing sample collection, the development of 3Rs focused regulatory policy, and humane end point determination.[Box: see text].

Determining the effect of photodegradation on film coated nifedipine tablets with terahertz based coating thickness measurements

Film coating of nifedipine tablets is commonly performed to reduce photo-degradation. The coating thickness of these tablets is a primary dictating factor of photo-stability. Terahertz spectroscopy enables accurate measurement of coating thickness. This study identifies a method to determine an end-point of a photo-protective coating process by using coating thickness measurements from terahertz time of flight spectroscopy (THz-TOF). For this method, nifedipine tablets, at different coating thicknesses, were placed in a photostability chamber. The illumination conditions of the coated tablets were adjusted based on the time duration of these tablets inside the chamber. A multiple linear regression model was developed with the coating thickness estimates from THz-TOF and illumination conditions information to predict the amount of drug remaining after photo-degradation (percent label claim). The prediction error of this model was 1.03% label claim in the range of 88.4–100.6% label claim. According to this model, acceptable levels of photo-protection in illumination conditions of up to approximately 700,000 lx hours was achieved at the end of the coating process (approximately 50 µm coating thickness) performed in this study. These results suggest THz-TOF as a viable process analytical technology tool for process understanding and end-point determination of a photo-protective coating process.

Vertebral Heart Score: A Useful Parameter in Determination of Resuscitation Endpoint in Dogs with Hemorrhagic Shock

BACKGROUND: GReliable prediction of patient response to fluid resuscitation is a crucial issue in the management of hemorrhagic shock. OBJECTIVES: This study was designed to investigate vertebral heart score (VHS) variation in fluid resuscitation of hemorrhagic shock patients and the feasibility of this method in determining resuscitation endpoint. METHODS: VHS values were assessed using previously published standard method in left to right lateral view. After induction of anesthesia (control assessments), hemorrhagic shock was induced by blood withdrawal to a mean arterial pressure of 40 to 50 mmHg within 30 minutes and then maintained in hypovolemic situation for an additional 30 minutes (second and third stages of assessments). Afterward, the dogs were randomly assigned to two groups which received 20 ml/kg lactated Ringer’s solution or 5 ml/kg Hydroxyethyl starch, in four consecutive 15 minute intervals (fourth stage of assessments). One hour after the last resuscitation step, final radiographic assessments were performed. RESUTLS: Hemorrhagic shock caused significant decrease in VHS values to a mean of 7.7 vertebrae (P<0.05). Following the fluid resuscitation VHS increased and returned to pre-shock values in both groups. CONCLUSIONS: This study confirms that the breed-specific VHS assessment can be a useful method in monitoring of patient’s response to fluid therapy and determination of resuscitation endpoint in dogs with hemorrhagic shock.

Determination of relevant endpoints to evaluate the in vivo barrier function in cutaneous health

Determination of relevant endpoints to evaluate the in vivo barrier function in cutaneous health

Shedding light on coatings: Real-time monitoring of coating quality at industrial scale

Optical Coherence Tomography (OCT) is increasingly being used for studies of pharmaceutical film coating. OCT allows fast and non-destructive analysis of the coating thickness and quality via high-resolution cross-sectional images. Information about both the coating thickness and the coating quality can be extracted. Most studies and OCT applications performed to date have been limited to off-line measurements and off-line computations of coating features based on data acquired in-line. This study examines OCT’s applicability to an industrial-scale pan coating process. Automated layer detection, classification and thickness calculation were executed in real time. To evaluate the system’s performance, runs with various tablet size, coating solution concentration and operating parameters were carried out and monitored. Our results indicate that, in addition to correct end-point determination, OCT enables real-time monitoring of the coating processes (thickness, homogeneity and roughness) and can support active process control by supplying information about the coating thickness and quality.

End point determination for spent nuclear fuel drying operations

When spent nuclear fuel is being dried ahead of either interim storage or long term disposal it is necessary to be able to confirm that the required level of dryness has been achieved. This has typically involved a vacuum rebound test however this method has certain limitations in terms of both reliability of the result and also by introducing an additional step that is time consuming and depending on the drying system used requires additional equipment at high system cost. It would be preferable if the end point and requisite dryness could be confirmed from online data readings recorded during the drying process.This paper presents the results of a number of vacuum drying tests using a benchtop drying rig in which online dew point, temperature, pressure and mass flow rate readings were compared to the results of vacuum rebound tests.Mass flow rate, pressure and dew point readings all showed cliff edge behaviour as the drying process progressed. Flow rate provided a good indicator of progress however it was clear from the behaviour that the resolution of the instrument was not sufficient to confirm dryness. Neither pressure nor dew point readings alone were capable of indicating whether a test would be passed successfully however it was found that in combination an envelope existed in which a vacuum rebound test was always passed.Testing of the same techniques for flowed gas drying methods was limited due to the lack of a suitable way of confirming whether dryness was achieved however there was an indication that dew point measurements would be capable of confirming that a set level of dryness had been achieved.

Clinical endpoints for efficacy studies

Well-established, validated and clinically meaningful primary and secondary endpoints are critical in advancing vaccines through proof of principal studies, licensure and pre-qualification. To that end, the field of vaccine development for Shigella, enterotoxigenic Escherichia coli (ETEC) as well as other enteric pathogens would benefit greatly from a focused review of clinical endpoints and the use of common endpoints across the field to enable study-to-study comparisons as well as comparative assessments between vaccine candidates. A workshop was conducted to review clinical endpoints from controlled human challenge studies, field studies in naïve adult travelers and pediatric studies in low-middle income countries and to develop a consensus on clinical endpoints for future vaccine trials.Following sequential presentations on different study designs (CHIM, travelers’ efficacy and pediatric efficacy), workshop participants broke into three simultaneous workgroups focused on those study designs to discuss a number of topics key to clinical endpoints specific to each study design. Previously utilized endpoints were reviewed with an eye towards potentially novel endpoints for future studies and consideration of the disease parameters and spectrum of disease targeted for prevention. The strength of support among workshop participants for the use of various endpoints is summarized as are recommendations for additional endpoints to be considered in future studies. It is anticipated that this report will facilitate endpoint determination in future efficacy trials of vaccine candidates.

A Novel Pharmacokinetic Bridging Strategy to Support a Change in the Route of Administration for Biologics

Determination of appropriate pharmacokinetic end point to bridge different dosing regimens is often a challenge when developing a new route of administration. Trough concentrations (Ctrough) are often considered the most relevant PK end point to predict efficacy (ACR20/DAS28) in the treatment of rheumatoid arthritis for biologics. However, no systematic research has been conducted to evaluate this approach. We developed a novel strategy to predict the most relevant PK variables that may be used to support a change in the route of administration for biological products. Our analysis indicated that matching only Ctrough when switching from intravenous dosing to subcutaneous dosing with decreasing dosing interval may result in a lower treatment response. If only average concentration (Cave) is considered as the relevant variable, our analysis showed that treatment response may be worsened when switching from subcutaneous dosing to intravenous dosing with increasing dosing interval. The study results demonstrated that matching a single pharmacokinetic end point (Ctrough or Cave) may not be sufficient to ensure efficacy when switching between intravenous dosing and subcutaneous dosing. A practical novel pharmacokinetic bridging approach is provided to support a change in the route of administration for biological products.

The Index of Ideality of Correlation (IIC): model for sweetness

The prediction of physicochemical and biochemical endpoints related to food, cosmetics, drug discovery, and medicine using computational approaches is relevant to the need of the modern society. The experimental determination of the endpoints is impossible for all necessary substances. The Index of Ideality of Correlation (IIC) is a criterion of predictive potential of a model. The index has been implemented in the CORAL software, which is a tool to build up quantitative structure—activity relationships. In the present work, two models for sweetness potential are built using this software. The first model is built without taking into account the IIC. The second model is built with taking into account the IIC. The results show that the IIC improves the predictive potential. This was confirmed in three computational experiments with random splits of the data related to sweetness into training and validation sets.

Refining humane endpoints in mouse models of disease by systematic review and machine learning-based endpoint definition.

Ideally, humane endpoints allow for early termination of experiments by minimizing an animal's discomfort, distress and pain, while ensuring that scientific objectives are reached. Yet, lack of commonly agreed methodology and heterogeneity of cut-off values published in the literature remain a challenge to the accurate determination and application of humane endpoints. With the aim to synthesize and appraise existing humane endpoint definitions for commonly used physiological parameters, we conducted a systematic review of mouse studies of acute and chronic disease models, which used body weight, temperature and/or sickness scores for endpoint definition. In the second part of the study, we used previously published and unpublished data on weight, temperature and sickness scores from mouse models of sepsis and stroke and applied machine learning algorithms to assess the usefulness of this method for parameter selection and endpoint definition across models. Studies were searched for in two electronic databases (MEDLINE/Pubmed and Embase). Out of 110 retrieved full-text manuscripts, 34 studies were included. We found large intra- and inter-model variance in humane endpoint determination and application due to varying animal models, lack of standardized experimental protocols and heterogeneity of performance metrics (part 1). Machine learning models trained with physiological data and sickness severity score or modified DeSimoni neuroscore identified animals with a high risk of death at an early time point in both mouse models of stroke (male: 93.2% at 72h post-treatment; female: 93.0% at 48h post-treatment) and sepsis (96.2% at 24h post-treatment), thus demonstrating generalizability in endpoint determination across models (part 2).

Determination of end point of fluid resuscitation using simplified lung ultrasound protocol in patients with septic shock

Context Fluid administration requires dynamic measures that are preferred over static ones as they are easy to apply and noninvasive. Thoracic ultrasound could be used in assessing extravascular lung water by visualizing the so-called B-lines. Aim To assess the role of a new simple ultrasound protocol in identifying the end point of fluid resuscitation in patients with septic shock. Settings and design A single-blinded randomized controlled trial was carried out on 80 consecutive adult patients with septic shock. Patients and methods Patients were divided into two groups: the first received fluid resuscitation according to early goal-directed therapy with a target central venous pressure of 8–12 mmHg, whereas the second received fluids guided by simplified lung ultrasound protocol till reaching a score of 16. Statistical analysis used IBM SPSS software package, version 20.0 was used for statistical analyses. Results The ultrasound score showed a negative significant weak correlation with the hypoxic index (Spearman’s r=−0.39, P=0.012), whereas it showed a positive moderate significant correlation with the central venous pressure readings (Spearman’s r=0.50, P=0.001), and positive moderate significant correlation with the congestion by chest radiography (Spearman’s r=0.47, P=0.002). A score of more than or equal to 10 in patients with septic shock with a sensitivity of 84.21% and specificity of 90.48% was concluded, upon which resuscitation should be terminated (area under the curve was 0.818 with a significant correlation of P=0.001). Conclusion Simplified lung ultrasound protocol could be used as an end point of fluid resuscitation in patients with septic shock to avoid fluid overload effects.

Scheduling and Control of a Wafer Transfer Robot for Foundry Equipment Innovation Competition

This paper presents a design and implementation of a wafer transfer robotic system for a Foundry Equipment Innovation Competition. In this system, a 4-DOF robotic arm was designed and constructed for wafer transfer between a cassette and processing chambers. The purpose of this competition was to promote intelligent automation for wafer fabrication, in which multiple wafers and chambers need to be handled simultaneously. A scheduling algorithm is proposed for efficient task execution of wafer to process recipes assigned during the competition. The task also features to integrate defect detection and endpoint determination of wafer processing. The robot was required to receive the processing data from the mission platform to determine the endpoint of wafer processing in a chamber and complete the recipe automatically. The online inspection algorithm detects wafer defects during the task execution and report to the task planner. The state of each wafer and chamber are taken into consideration for scheduling in order to complete the wafer fabrication in an efficient and flexible manner. The developed robotic system spent 9 minutes to complete the assigned mission of transferring 6 wafers among multiple chambers and 2 cassettes and achieved 93.4% defect-detection rate in the competition.

A rational approach of early humane endpoint determination in a murine model for cholestasis_suppl

Reduction of animal suffering during in vivo experiments is usually ensured by continuously monitoring the health status using a score sheet and by applying humane endpoints. However, most studies do not evaluate the plausibility of score sheets and do not attempt to reduce the suffering of animals by determining earlier and, therefore, more humane endpoints. The present study uses data from BALB/cANCrl mice after bile duct ligation to retrospectively analyze which score sheet criteria are informative to determine humane endpoints. The performance of each single as well as com­binations of multiple animal welfare parameters was analyzed by a Cox proportional-hazards model followed by Harrell’s concordance index. The addition of behavioral parameters, such as burrowing activity, helped to define a more humane early endpoint for euthanizing these animals. Using this approach, we determined that a body weight loss of 10-20% combined with a reduction of burrowing activity by more than 79.4% was able to predict that these animals would die within two days. Thus, this approach successfully determined an earlier humane endpoint and will reduce the suffering of animals in future experiments. Application of such an approach or similar methods can contribute to the refinement of various animal experiments.

A rational approach of early humane endpoint determination in a murine model for cholestasis.

Reduction of animal suffering during in vivo experiments is usually ensured by continuously monitoring the health status using a score sheet and by applying humane endpoints. However, most studies do not evaluate the plausibility of score sheets and do not attempt to reduce the suffering of animals by determining earlier and, therefore, more humane endpoints. The present study uses data from BALB/cANCrl mice after bile duct ligation to retrospectively analyze which score sheet criteria are informative to determine humane endpoints. The performance of each single as well as com­binations of multiple animal welfare parameters was analyzed by a Cox proportional-hazards model followed by Harrell’s concordance index. The addition of behavioral parameters, such as burrowing activity, helped to define a more humane early endpoint for euthanizing these animals. Using this approach, we determined that a body weight loss of 10-20% combined with a reduction of burrowing activity by more than 79.4% was able to predict that these animals would die within two days. Thus, this approach successfully determined an earlier humane endpoint and will reduce the suffering of animals in future experiments. Application of such an approach or similar methods can contribute to the refinement of various animal experiments.

A Novel Whole Blood Point-of-Care Coagulometer to Measure the Effect of Direct Oral Anticoagulants and Heparins.

The direct oral anticoagulants (DOACs) currently require no monitoring for routine therapy of atrial fibrillation or venous thromboembolism. Measurement of activity, however, may be important in patients with major and life-threatening bleeding, patients needing emergent surgery, in reversal situations, or in patients at high risk of bleeding or thrombosis due to underlying conditions. For these patients, a widely available and rapid turnaround assay would be optimal. To date, there is no such assay available, especially for the direct factor Xa inhibitors. This report describes the performance of a new, rapid turnaround, point-of-care (PoC) assay for measuring the activity of a range of anticoagulants, including DOACs and heparins, in emergency situations and for routine measurement in high-risk patients. Perosphere Technologies' PoC coagulometer is a handheld instrument that performs individual coagulation tests on samples of fresh whole blood (∼10 µL) with clotting activated by glass contact and endpoint determination performed by infrared spectroscopy. In preclinical studies using rats anticoagulated with therapeutic doses of edoxaban or enoxaparin, the PoC coagulometer showed a strong linear correlation between pharmacokinetic parameters and clotting time with edoxaban (r 2 = 0.994) and with enoxaparin (r 2 = 0.967). These preclinical results suggest that this PoC coagulometer would be ideal to assess the pharmacodynamic effects of anticoagulants and their reversal agents. The PoC bedside instrument delivers results within minutes and requires no more than a drop of whole blood. Studies are underway to confirm these results in humans and to further characterize the performance of the instrument.

Glaucoma - Next Generation Therapeutics: Impossible to Possible.

The future of next generation therapeutics for glaucoma is strong. The recent approval of two novel intraocular pressure (IOP)-lowering drugs with distinct mechanisms of action is the first in over 20years. However, these are still being administered as topical drops. Efforts are underway to increase patient compliance and greater therapeutic benefits with the development of sustained delivery technologies. Furthermore, innovations from biologics- and gene therapy-based therapeutics are being developed in the context of disease modification, which are expected to lead to more permanent therapies for patients. Neuroprotection, including the preservation of retinal ganglion cells (RGCs) and optic nerve is another area that is actively being explored for therapeutic options. With improvements in imaging technologies and determination of new surrogate clinical endpoints, the therapeutic potential for translation of neuroprotectants is coming close to clinical realization. This review summarizes the aforementioned topics and other related aspects.

Determination of the intramuscular motor endpoint for effective administration of botulinum toxin in the treatment of spasticity

Determination of the intramuscular motor endpoint for effective administration of botulinum toxin in the treatment of spasticity