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1
Arunabala, Dr C., P. V. Sai Ranjitha, Bomminayuni Likhitha Gunturu Sravya, Bonagiri Navyasree, and Arumalla Mounika. "Design of Diversified Low Power and High-Speed Comparators using 45nm Cmos Technology." International Journal of Innovative Technology and Exploring Engineering 11, no. 5 (April 30, 2022): 27–31. http://dx.doi.org/10.35940/ijitee.e9849.0411522.
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At Present, portable battery-operated devices are enhancing due to low power consumption and high-speed applications, The designed circuit with feedback are used to design novel circuits. If the comparator having feedback are without clock signal. The comparators are mainly designed to minimize the power consumption and with good accuracy because of clock signal, if the clock signal is there, it is used to drive the circuit with low current. But in the existed design the circuit is with high power and current. These drawbacks are overcome by using the projected designed comparator. The Projected comparator design is with reduced power consumption, propagation delay, currents and with a smaller number of transistors. The comparators are useful in analog to digital converters. And this is simulated by using 45 nm CMOS technology Cadence Virtuoso tool.
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Chavoshisani, Reza, Mohammad Hossein Moaiyeri, and Omid Hashemipour. "A high-performance low-voltage current-mode min/max circuit." COMPEL: The International Journal for Computation and Mathematics in Electrical and Electronic Engineering 34, no. 4 (July 6, 2015): 1172–83. http://dx.doi.org/10.1108/compel-10-2014-0245.
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Purpose – Current-mode approach promises faster and more precise comparators that lead to high-performance and accurate winner-take-all circuits. The purpose of this paper is to present a new high-performance, high-accuracy current-mode min/max circuit for low-voltage applications. In addition, the proposed circuit is designed based on a new efficient high-resolution current conveyor-based fully differential current comparator. Design/methodology/approach – The proposed design detects the min and max values of two analog current signals by means of a current comparator and a logic module. The comparator compares the values of the input current signals accurately and generates two digital control signals and the logic module determines the min and max values based on the controls signals. In addition, an accurate current copy module is utilized to copy the input current signals and convey them to the comparator and the logic module. Findings – The results of the comprehensive simulations, conducted using HSPICE with the TSMC 90 nm CMOS technology, demonstrate the high-performance and robust operation of the proposed design even in the presence of process, temperature, input current and supply voltage variations. For a case in point, for 5 μA differential input current the average propagation delay and power consumption of the proposed circuit are attained as 150 ps and 150 µW, respectively, which leads to more than 64 percent improvement in terms of power-delay product as compared with the most efficient design, previously presented in the literature. Originality/value – A new efficient structure for current-mode min-max circuit is proposed based on a novel current comparator design which is accurate, high-performance and robust to process, voltage and temperature variations.
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TANG, XIAN, and KONG PANG PUN. "A NOVEL SWITCHED-CURRENT SUCCESSIVE APPROXIMATION ADC." Journal of Circuits, Systems and Computers 20, no. 01 (February 2011): 15–27. http://dx.doi.org/10.1142/s0218126611007049.
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A novel switched-current successive approximation ADC is presented in this paper with high speed and low power consumption. The proposed ADC contains a new high-accuracy and power-efficient switched-current S/H circuit and a speed-improved current comparator. Designed and simulated in a 0.18-μm CMOS process, this 8-bit ADC achieves 46.23 dB SNDR at 1.23 MS/s consuming 73.19 μW under 1.2 V voltage supply, resulting in an ENOB of 7.38-bit and an FOM of 0.357 pJ/Conv.-step.
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Fathi, Amir, Abdollah Khoei, and Khayrollah Hadidi. "High Speed Min/Max Architecture Based on a Novel Comparator in 0.18-μm CMOS Process." Journal of Circuits, Systems and Computers 24, no. 04 (March 4, 2015): 1550048. http://dx.doi.org/10.1142/s0218126615500486.
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This paper describes the design of a high speed min/max architecture based on a new current comparator. The main advantage of the proposed circuit which employs a novel preamplifier-latch comparator is the higher operating frequency feature in comparison with previous works. Because the comparator can work in voltage mode, the min/max structure can be redesigned either in voltage or current mode. The designed comparator is refreshed without any external clock. Therefore, it does not degrade the speed performance of proposed min/max structure. These features along with low power consumption qualify the proposed architecture to be widely used in high speed fuzzy logic controllers (FLCs). Post-layout simulation results confirm 3.4 GS/s comparison rate with 9-bit resolution for a 0.9 V peak-to-peak input signal range for the comparator and 800 MHz operating frequency for min/max circuit. The power consumption of whole structure is 912 μW from a 1.8 V power supply using TSMC 0.18-μm CMOS technology.
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Monika and Poornima Mittal. "A novel modified current comparator based on extremely low voltage high compliance current mirror." International Journal of Information Technology 14, no. 1 (October 28, 2021): 323–31. http://dx.doi.org/10.1007/s41870-021-00823-7.
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Ouremchi, Mounir, Karim El Khadiri, Ahmed Tahiri, and Hassan Qjidaa. "Design of a Novel Current Mode Charge Pump for Very-Low-Voltage Applications in 130 nm SOI-BCD Technology." International Journal of Circuits, Systems and Signal Processing 15 (May 18, 2021): 461–69. http://dx.doi.org/10.46300/9106.2021.15.50.
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A novel charge pump with current mode control suitable to work under a very-low-voltage supply is proposed in this paper. The proposed charge pump consists of two sections. The first section is a power switches stage which consists of seven cascaded DEPMOS power switches. The second section is a low voltage stage which consists of a Low Voltage Level Shifter, Current Mode control, Follower Amplifier, Error Amplifier, Soft Start Comparator, and Skip mode & Over Voltage Comparator. The charge pump has been designed, simulated, and layout in Cadence using TSMC 130 nm SOI technology with LDMOS transistors, which have very low on-resistance. The input range of the charge pump is 2.7– 4.4 V, and it can supply up to 100 mA load current. The maximum efficiency is 90%, and the chip area is only 0.597 mm².
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Wang, Cheng, Zhanpeng Yang, Xinpeng Xing, Quanzhen Duan, Xinfa Zheng, and Georges Gielen. "A 10-Bit 400 MS/s Dual-Channel Time-Interleaved SAR ADC Based on Comparator Multiplexing." Electronics 12, no. 19 (September 27, 2023): 4062. http://dx.doi.org/10.3390/electronics12194062.
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This paper proposes a 10-bit 400 MS/s dual-channel time-interleaved (TI) successive approximation register (SAR) analog-to-digital converter (ADC) immune to offset mismatch between channels. A novel comparator multiplexing structure is proposed in our design to mitigate comparator offset mismatch between channels and improve ADC dynamic performance. Compared to traditional TI-SAR ADC utilizing offset calibration technique, hardware and power consumption overhead are minimized in our design. In addition, a split capacitive digital-to-analog converter (CDAC) and a double-tail dynamic comparator using the clock decoupling technique were applied to eliminate comparator common mode input voltage shift, ensuring conversion accuracy and boosting speed. A 400 MS/s 10-bit dual-channel TI-SAR ADC with comparator multiplexing was designed in 40 nm CMOS and compared to the conventional one. The simulated ADC ENOB and SFDR with 6σ offset mismatch were improved from 5.0-bit and 32.2 dB to 9.7-bit and 77.2 dB, respectively, confirming the merits of the proposed design compared to current state-of-the-art works.
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He, Lin, Gang Li, and Meng Tang. "Relaxation Oscillator Exploiting PTAT Hysteresis of Differential Schmitt Trigger." Journal of Circuits, Systems and Computers 24, no. 10 (October 25, 2015): 1550147. http://dx.doi.org/10.1142/s0218126615501479.
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In this paper, we proposed a novel relaxation oscillator to address the frequency variation caused by the comparator delay. The conventional operational transconductance amplifiers (OTAs)-comparator is replaced with a Schmitt trigger to significantly reduce the delay. This Schmitt trigger is implemented by a differential structure operating in the subthreshold region to generate a proportional to absolute temperature (PTAT) hysteresis. Both the voltage reference and the current source are made PTAT as well. The proposed oscillator can be made ultra-low power and have excellent frequency stability over process, voltage and temperature (PVT) variation.
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Bhatia, Veepsa, Neeta Pandey, and Asok Bhattacharyya. "High Speed Power Efficient CMOS Inverter Based Current Comparator in UMC 90 nm Technology." International Journal of Electrical and Computer Engineering (IJECE) 6, no. 1 (February 1, 2016): 90. http://dx.doi.org/10.11591/ijece.v6i1.8693.
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A novel power-speed efficient current comparator is proposed in this paper. It comprises of only CMOS inverters in its structure, employing a simple biasing method. The structure offers simplicity of design. It posesses the very desirable features of high speed and low power dissipation, making this structure a highly desirable one for various current mode applications. The simulations have been performed using UMC 90 nm CMOS technology and the results demonstrate the propagation delay of about 3.1 ns and the average power consumption of 24.3 µW for 300 nA input current at supply voltage of 1V.
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Bhatia, Veepsa, Neeta Pandey, and Asok Bhattacharyya. "High Speed Power Efficient CMOS Inverter Based Current Comparator in UMC 90 nm Technology." International Journal of Electrical and Computer Engineering (IJECE) 6, no. 1 (February 1, 2016): 90. http://dx.doi.org/10.11591/ijece.v6i1.pp90-98.
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A novel power-speed efficient current comparator is proposed in this paper. It comprises of only CMOS inverters in its structure, employing a simple biasing method. The structure offers simplicity of design. It posesses the very desirable features of high speed and low power dissipation, making this structure a highly desirable one for various current mode applications. The simulations have been performed using UMC 90 nm CMOS technology and the results demonstrate the propagation delay of about 3.1 ns and the average power consumption of 24.3 µW for 300 nA input current at supply voltage of 1V.
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Bchir, Mounira, Thouraya Ettaghzouti, and Néjib Hassen. "A Novel High Frequency Low Voltage Low Power Current Mode Analog to Digital Converter Pipeline." Journal of Low Power Electronics 15, no. 4 (December 1, 2019): 368–78. http://dx.doi.org/10.1166/jolpe.2019.1621.
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This paper introduces a novel structure for the realization of a low voltage, low power current-mode analog to the digital converter (ADC) pipeline (12 bits). The proposed structure of the ADC is based on a novel design of a current comparator and Digital to Analog Converter (DAC) structure. This modification allows us to reach a higher speed, lower voltage, and lower power dissipation. ELDO simulators using 0.18 μm, CMOS and TSMC parameters are performed to confirm the workability of this architecture. The proposed ADC is powered with a 1 V supply voltage. It is characterized by wide conversion frequency (350 MHz) and low power consumption that is 2.76 mW.
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Huang, S., Peijun Liu, Quanzhen Duan, Yuemin Ding, and Zhen Meng. "A −4–4 V Input Common-Mode Range Bidirectional Current Shunt Monitor." Journal of Circuits, Systems and Computers 29, no. 14 (March 25, 2020): 2050221. http://dx.doi.org/10.1142/s0218126620502217.
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This study describes a novel bidirectional current shunt monitor (CSM) circuit operating at both positive and negative common-mode (CM) voltages. The proposed CSM circuit mainly consists of two comparators, three error amplifiers, several current-mirror transistors and a few resistors. One comparator is used to detect current flowing direction, and the other one is utilized to ensure good operation of CSM circuit with both positive and negative CM voltages. The proposed CSM circuit has been implemented in SMIC 0.18[Formula: see text][Formula: see text]m standard CMOS process and its performances have been verified by simulations. The simulated results show that the proposed CSM circuit, at a supply voltage of 5[Formula: see text]V and with an input CM voltage range from [Formula: see text] to 4[Formula: see text]V, can sense a voltage difference of 4–40[Formula: see text]mV and keep a constant scaled gain of 100[Formula: see text]V/V. The gain error is less than 0.65% and the common-mode rejection ratio (CMRR) is higher than 130[Formula: see text]dB at 1[Formula: see text]kHz. Simulation results show that the output voltage of CSM circuit varies linearly with the CSM input sense voltage.
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Bhatia, Veepsa, Neeta Pandey, and Asok Bhattacharyya. "Modelling and Design of Inverter Threshold Quantization based Current Comparator using Artificial Neural Networks." International Journal of Electrical and Computer Engineering (IJECE) 6, no. 1 (February 1, 2016): 320. http://dx.doi.org/10.11591/ijece.v6i1.8700.
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<p>Performance of a MOS based circuit is highly influenced by the transistor dimensions chosen for that circuit. Thus, proper dimensioning of the transistors plays a key role in determining its overall performance. While choosing the dimension is critical, it is equally difficult, primarily due to complex mathematical formulations that come into play when moving into the submicron level. The drain current is the most affected parameter which in turn affects all other parameters. Thus, there is a constant quest to come up with techniques and procedure to simplify the dimensioning process while still keeping the parameters under check. This study presents one such novel technique to estimate the transistor dimensions for a current comparator structure, using the artificial neural networks approach. The approach uses Multilayer perceptrons as the artificial neural network architectures. The technique involves a two step process. In the first step, training and test data are obtained by doing SPICE simulations of modelled circuit using 0.18μm TSMC CMOS technology parameters. In the second step, this training and test data is applied to the developed neural network architecture using MATLAB R2007b.</p>
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Bhatia, Veepsa, Neeta Pandey, and Asok Bhattacharyya. "Modelling and Design of Inverter Threshold Quantization based Current Comparator using Artificial Neural Networks." International Journal of Electrical and Computer Engineering (IJECE) 6, no. 1 (February 1, 2016): 320. http://dx.doi.org/10.11591/ijece.v6i1.pp320-329.
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<p>Performance of a MOS based circuit is highly influenced by the transistor dimensions chosen for that circuit. Thus, proper dimensioning of the transistors plays a key role in determining its overall performance. While choosing the dimension is critical, it is equally difficult, primarily due to complex mathematical formulations that come into play when moving into the submicron level. The drain current is the most affected parameter which in turn affects all other parameters. Thus, there is a constant quest to come up with techniques and procedure to simplify the dimensioning process while still keeping the parameters under check. This study presents one such novel technique to estimate the transistor dimensions for a current comparator structure, using the artificial neural networks approach. The approach uses Multilayer perceptrons as the artificial neural network architectures. The technique involves a two step process. In the first step, training and test data are obtained by doing SPICE simulations of modelled circuit using 0.18μm TSMC CMOS technology parameters. In the second step, this training and test data is applied to the developed neural network architecture using MATLAB R2007b.</p>
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Gagliardi, Francesco, Giuseppe Manfredini, Andrea Ria, Massimo Piotto, and Paolo Bruschi. "Low-Phase-Noise CMOS Relaxation Oscillators for On-Chip Timing of IoT Sensing Platforms." Electronics 11, no. 11 (June 6, 2022): 1794. http://dx.doi.org/10.3390/electronics11111794.
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The design of low-phase-noise fully integrated frequency references is often a critical aspect in the development of low-cost integrated circuits for communication interfaces, sensing platforms, and biomedical applications. This work first discusses relaxation oscillator topologies and design approaches aimed at minimizing the phase noise; then, a single-comparator low-phase-noise RC relaxation oscillator is proposed, featuring a novel comparator self-threshold-adjustment technique. The oscillator was designed for a 10 MHz oscillation frequency. Electrical simulations performed on a 0.18 μm CMOS design confirmed that the proposed technique effectively rejects the flicker component of the comparator noise, allowing for a 152 dBc/Hz figure of merit at a 1 kHz offset frequency. The standard deviation of the jitter accumulated across 10k oscillation cycles is lower than 4 ns. The simulated current consumption of the circuit is equal to 50.8 μA with a 1.8 V supply voltage. The temperature sensitivity of the oscillation frequency is also notably low, as its worst-case value across process corners is equal to −20.8 ppm/°C from −55 °C to 125 °C.
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WAWRYN, KRZYSZTOF, ROBERT SUSZYNSKI, and BOGDAN STRZESZEWSKI. "A LOW POWER DIGITALLY ERROR CORRECTED 2.5 BIT PER STAGE PIPELINED A/D CONVERTER USING CURRENT-MODE SIGNALS." Journal of Circuits, Systems and Computers 20, no. 01 (February 2011): 29–43. http://dx.doi.org/10.1142/s0218126611007050.
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This paper, presents a novel low power current mode 9 bit pipelined a/d converter. The a/d converter structure is composed of three 2.5 bit stages and one 3 bit stage operating in current mode and a final comparator which converts the analog current signal into a digital voltage signal. All the building blocks of the converter were designed in CMOS AMS 0.35 μm technology, simulated, and then a prototype converter was manufactured and measured to verify the proposed concept. The performances of the converter are compared to performances of known voltage-mode switched-capacitance and current-mode switched-current converter structures. Low power consumption and small chip area are the advantages of the proposed converter.
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Breisinger, Kristy, Khristina Harrell, Laura Serena, and Thomas E. Serena. "A prospective clinical pilot study comparing two post-operative dressings in the treatment of surgical incisions in volunteers." Journal of Wound Care 31, Sup9 (September 1, 2022): S28—S32. http://dx.doi.org/10.12968/jowc.2022.31.sup9.s28.
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Objective: Surgical site infections (SSIs) are one of the leading causes of post-operative morbidity and mortality worldwide. The original post-operative dressing, gauze taped in place, did not protect the incision from contamination. A recent clinical trial demonstrated that transparent films were superior to gauze in reducing SSIs. Transparent films are semi-occlusive (semi-permeable, transparent). They protect the incision from contamination; however, one of the drawbacks of current films is that they may become dislodged during daily activities, such as showering. Patients may not realise that the integrity of the dressing has been compromised, leading to soiling of the incision and possible infection. DrySee (DrySee Inc., US) is a novel film dressing with a colorimetric indicator that alerts the patient when the dressing has been compromised. Method: This trial compared the film dressing with the indicator (DSD) to a commonly used post-operative dressing comparator (Tegaderm + Pad; 3M, US). A 1.5cm incision was made in the volar forearm of volunteers. The incisions were randomly treated with the DSD or comparator dressing. Results: A cohort of 20 volunteer patients was recruited. The DSD had a greater wear time and patients reported that the DSD dressing stayed in place better during activities compared to the comparator. Conclusion: Overall, 75% of patients preferred DSD and 25% preferred the comparator.
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Wen Chek, Leong, Saad Mekhilef, Erwan Sulaiman, and Macwien Krishnamurthi. "Design of ramp-time current control with dynamic fuzzy bandwidth for wireless power transmission." International Journal of Microwave and Wireless Technologies 8, no. 8 (August 14, 2015): 1173–82. http://dx.doi.org/10.1017/s1759078715001270.
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This paper presents a novel experimental simulation of ramp-time current control with fuzzy bandwidth for wireless power transmission (WPT) systems. A fuzzy logic control algorithm was designed based on the structure of ramp-time current control in active power filters through simulation of ramp-time bandwidth variation to dynamically adjust the loop width of the ramp-time comparator. Ramp-time current control is the most suitable over other current control techniques and is thus selected for the experiment. Implementation of this approach prevents over-limit of switching frequency and enhances dynamic responses, resulting in long lifespan of power switches and smooth output for WPT systems. Finally, the hypothesis and simulation results were verified by analyzing the prototype model and experiment results.
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Minakshi Sanadhya, Minakshi Sanadhya, and Devendra Kumar Sharma Minakshi Sanadhya. "Adiabatic Logic Based Energy Efficient Architecture of 1-Bit Magnitude Comparator for IOT Applications." 網際網路技術學刊 23, no. 7 (December 2022): 1643–49. http://dx.doi.org/10.53106/160792642022122307018.
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<p>The Internet of Things (IoT) applies the sensors and microcontrollers and links them through the internet. The eventual objective of low-power devices for Internet of Things is to lesser the overall system power and to extend battery life. For the development of energy efficient IoT devices, novel adiabatic techniques are proposed. By improving the performance of the comparator, one can improvise the whole system performance. The efficacy of computing devices depends on the performance of arithmetic circuits, including comparator. This paper proposes 1-bit comparator design using adiabatic techniques such as DC-DB PFAL (Direct current diode-based positive feedback adiabatic logic) and MPFAL (Modify positive feedback adiabatic logic) which are well-suited with an extensive range of applications (e.g. IoT sensors and an inbuilt analog to digital converter). For performance analysis, the results are compared together along with the other adiabatic and non adiabatic designs already reported in the literature. This paper proposes a way to decrease the dissipation of power and transistor count in binary circuits as it is one of the primary concerns. From the results, it is found that the design using DC-DB PFAL logic shows an improvement in power-delay-product of 69%, 94% and 90% compared to MPFAL, PFAL and ECRL techniques respectively.</p> <p> </p>
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Koopmeiners, Joseph S., and Brian P. Hobbs. "Detecting and accounting for violations of the constancy assumption in non-inferiority clinical trials." Statistical Methods in Medical Research 27, no. 5 (September 1, 2016): 1547–58. http://dx.doi.org/10.1177/0962280216665418.
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Randomized, placebo-controlled clinical trials are the gold standard for evaluating a novel therapeutic agent. In some instances, it may not be considered ethical or desirable to complete a placebo-controlled clinical trial and, instead, the placebo is replaced by an active comparator with the objective of showing either superiority or non-inferiority to the active comparator. In a non-inferiority trial, the experimental treatment is considered non-inferior if it retains a pre-specified proportion of the effect of the active comparator as represented by the non-inferiority margin. A key assumption required for valid inference in the non-inferiority setting is the constancy assumption, which requires that the effect of the active comparator in the non-inferiority trial is consistent with the effect that was observed in previous trials. It has been shown that violations of the constancy assumption can result in a dramatic increase in the rate of incorrectly concluding non-inferiority in the presence of ineffective or even harmful treatment. In this paper, we illustrate how Bayesian hierarchical modeling can be used to facilitate multi-source smoothing of the data from the current trial with the data from historical studies, enabling direct probabilistic evaluation of the constancy assumption. We then show how this result can be used to adapt the non-inferiority margin when the constancy assumption is violated and present simulation results illustrating that our method controls the type-I error rate when the constancy assumption is violated, while retaining the power of the standard approach when the constancy assumption holds. We illustrate our adaptive procedure using a non-inferiority trial of raltegravir, an antiretroviral drug for the treatment of HIV.
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Kaul, Nalini, Kathleen G. Palma, Stewart S. Silagy, J. John Goodman, and Jack Toole. "North American Efficacy and Safety of a Novel Pediculicide Rinse, Isopropyl Myristate 50% (Resultz)." Journal of Cutaneous Medicine and Surgery 11, no. 5 (September 2007): 161–67. http://dx.doi.org/10.2310/7750.2007.00045.
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Background: Head lice infestations are a major nuisance in school-aged children and are a worldwide public health problem. There are growing concerns about the effectiveness of current treatments owing to increasing resistance, safety, and patient noncompliance. A safe, easy to use, effective alternative is needed. Objective: A pediculicide rinse, 50% isopropyl myristate (IPM), was assessed in two phase 2 trials conducted in North America. The first trial was a nonrandomized (proof of concept) trial without a comparator conducted in Winnipeg, Canada. The second trial, conducted in the United States, was an evaluator-blinded, randomized superiority trial comparing 50% IPM rinse with a positive control (RID; pyrethrin 0.33%, piperonyl butoxide 4%). The primary end points were to determine the safety and efficacy of 50% IPM as a pediculicide rinse. Methods: Subjects meeting inclusion criteria were enrolled in the above-mentioned trials with efficacy end points 7 and 14 days post-treatment. Subjects were also evaluated on days 0, 7, 14, and 21 for the presence of erythema and edema using the Modified Draize Scale. Other comments associated with the safety evaluation (ie, pruritus) were collected. Results: IPM was found to be effective in the proof of concept study and comparator trial using a positive control. IPM was also well tolerated, with minimal adverse events. All adverse events were mild, resolving by completion of the study. Conclusion: Data suggest that IPM is a safe and effective therapy for the treatment of head lice in children and adults. IPM's mechanical mechanism of action makes development of lice resistance unlikely.
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Waloyo, Hery Tri, U. Ubaidillah, Dominicus Danardono Dwi Prija Tjahjana, Muhammad Nizam, and Muhammad Aziz. "A Novel Approach on the Unipolar Axial Type Eddy Current Brake Model Considering the Skin Effect." Energies 13, no. 7 (March 27, 2020): 1561. http://dx.doi.org/10.3390/en13071561.
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The braking torque mathematical modelling in electromagnetic eddy current brake (ECB) often ignores the skin effect that occurrs during operation. However this phenomenon can not be simply neglected. Therefore, this paper presents a mathematical model of braking torque for a unipolar axial type of ECB system with a non-magnetic disk, which considers the skin effects. The use of mathematical models that consider the existence of skin effects is significant in approaching the braking torque according to the actual condition. The utilization of generic calculations to the model of the ECB braking torque leads to invalid results. Hence, in this paper, the correction factor was added to improve the braking torque calculation as a comparator to the proposed equation. However, the modification and addition of the correction factor were only valid to estimate the low-speed regimes of torque, but very distant for the high-speed condition. From the comparison of calculated values using analytical and 3D modelling, the amount of braking torque at a low speed was found to have an average error for the equation using a correction factor of 1.78 Nm, while after repairing, a value of 1.16 Nm was obtained. For the overall speed, an average error of 14.63 Nm was achieved, while the proposed equation had a small difference of 1.79 Nm. The torque difference from the calculation results of the proposed model with the measurement value in the experiment was 4.9%. Therefore, it can be concluded that the proposed equation provided a better braking torque value approach for both low and high speeds.
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Enck, Paul, Sibylle Klosterhalfen, Katja Weimer, Björn Horing, and Stephan Zipfel. "The placebo response in clinical trials: more questions than answers." Philosophical Transactions of the Royal Society B: Biological Sciences 366, no. 1572 (June 27, 2011): 1889–95. http://dx.doi.org/10.1098/rstb.2010.0384.
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Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This ‘additive model’ is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in ‘comparator’ studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.
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Wolf, Andrew B., and Enrique Alvarez. "Ublituximab: A Novel Anti-CD20 Therapy for Multiple Sclerosis." US Neurology 18, no. 2 (2022): 117. http://dx.doi.org/10.17925/usn.2022.18.2.117.
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Ublituximab is a novel anti-CD20 therapy developed for the treatment of patients with multiple sclerosis. It is a glycoengineered chimeric antibody with a novel epitope on CD20, with high antibody-dependent cell-mediated cytotoxicity. Maintenance doses are administered every 6 months over an hour, providing a convenient dosing regimen. The identical phase III randomized, double-blind, active comparator to teriflunomide trials ULTIMATE I and II were completed in early 2022. ULTIMATE I and II, respectively, demonstrated that ublituximab had a strong clinical effect, with annualized relapse rates of 0.08 and 0.09 or reductions of 59% and 49% over teriflunomide. In addition, in ULTIMATE I and II, radiographic efficacy similarly reduced contrast-enhancing lesions by 97% and 96% and new/enlarging T2 lesions by 92% and 90%, respectively. Although ublituximab did not decrease confirmed disability progression in a pooled analysis of both studies, there was an increase in the confirmed disability improvement. Ublituximab was well tolerated, including infusion reactions that were predominantly mild and only seen with the first infusion. Further long-term safety data, as well as relative efficacy compared with current anti-CD20 therapies, will need to be evaluated in the real-world setting if ublituximab is to be approved as expected in December 2022.
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Liu, Kan, Lenian He, and Jianping Qiu. "A Digital Controller Based on Primary Side Regulation with Improved Accuracy for LED Application." Journal of Circuits, Systems and Computers 24, no. 03 (February 10, 2015): 1550034. http://dx.doi.org/10.1142/s0218126615500346.
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A digital controller for LED driver is presented. The controller is used in the flyback converter which works in discontinuous current mode (DCM). A comparator is adopted to shape the auxiliary winding voltage based on traditional primary side regulation (PSR). A five-states finite state machine (FSM) is designed to deal with the shaped auxiliary winding signal. The FSM extracts the system time information from the shaped signal and controls all the sequences in the whole system. To achieve high accuracy of the output current, an adaptive delay compensation scheme is adopted. A LED prototype whose typical output power is 7 W is used in both simulation and experiment to demonstrate the effectiveness of this novel digital controller. The measurement results show that the line regulation when the input ac voltage varies from 85–265 V is 3.4% and the load regulation when the load varies from 3–10 LEDs is 2.5%.
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Ding, Yew Yoong. "Risk Adjustment: Towards Achieving Meaningful Comparison of Health Outcomes in the Real World." Annals of the Academy of Medicine, Singapore 38, no. 6 (June 15, 2009): 552–58. http://dx.doi.org/10.47102/annals-acadmedsg.v38n6p552.
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Health outcomes evaluation seeks to compare a new treatment or novel programme with the current standard of care, or to identify variation of outcomes across different healthcare providers. In the real world, it is not always possible to conduct randomised controlled trials to address the issue of comparator groups being different with respect to baseline risk factors for the outcomes. Therefore, risk adjustment is required to address patient factors that may lead to biases in estimates of treatment effects. It is essential when conducting outcomes evaluation of more than trivial significance. Risk adjustment begins by asking 4 questions: what outcome, what time frame, what population, and what purpose. Next, design issues are considered. This involves choosing the data source, planning data collection, defining the sample required, and selecting the variables carefully. Finally, analytical issues are considered. Regression modelling is central to every analytic strategy. Other methods that may augment regression include restriction, stratification, propensity scores, instrumental variables, and difference-in-differences. The construction of risk adjustment models is an iterative process requiring both art and science. Derived models should be validated. Limitations of risk adjustment include reliance on data availability and quality, imperfect method, ineffectiveness when comparators are very different, and sensitivity to different methods used. Thoughtful application of risk adjustment can improve the validity of comparisons between different treatments, programmes and providers. The extent of risk adjustment should be guided by its purpose. Finally, its methodology should be made explicit, so that informed readers can judge the robustness of results obtained. Key words: Health Services Research, Outcome assessement, Regression analysis, Risk adjustment
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Kato, Norihito, Fukashi Morishita, Satoshi Okubo, and Masao Ito. "Circuit Techniques to Improve Low-Light Characteristics and High-Accuracy Evaluation System for CMOS Image Sensor." Sensors 22, no. 16 (August 12, 2022): 6040. http://dx.doi.org/10.3390/s22166040.
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The surveillance cameras we focus on target the volume zone, and area reduction is a top priority. However, by simplifying the ADC comparator, we face a new RUSH current issue, for which we propose a circuit solution. This paper proposes two novel techniques of column-ADC for surveillance cameras to improve low-light characteristics. RUSH current compensation reduces transient current consumption fluctuations during AD conversion and utilizing timing shift ADCs decreases the number of simultaneously operating ADCs. These proposed techniques improve low-light characteristics because they reduce the operating noise of the circuit. In order to support small signal measurement, this paper also proposes a high-accuracy evaluation system that can measure both small optical/electrical signals in low-light circumstances. To demonstrate these proposals, test chips were fabricated using a 55 nm CIS process and their optical/electrical characteristics were measured. As a result, low-light linearity as optical characteristics were reduced by 63% and column interference (RUSH current) as an electrical characteristic was also reduced by 50%. As for the high-accuracy evaluation system, we confirmed that the inter-sample variation of column interference was 0.05 LSB. This ADC achieved a figure-of-merit (FoM) of 0.32 e-·pJ/step, demonstrating its usefulness for other ADC architectures while using a single-slope-based simple configuration.
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Guo, Xu Dong, Chao Ruan, Bin Ge, Rong Guo Yan, and Ying Liu. "Magnetic Generator with Automatic Gain Regulation in a Wireless Tracking System for a Capsule Endoscope." Applied Mechanics and Materials 401-403 (September 2013): 1393–96. http://dx.doi.org/10.4028/www.scientific.net/amm.401-403.1393.
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To track a capsule endoscope, a novel measuring method based on alternating magnetic field is presented. The signal-to-noise ratio of the magnetic sensor decreases sharply with the increasing tracking distance. Thus, a magnetic generator with automatic gain regulation is designed to improve the localization precision. It is composed of a microcontroller, a DA converter, a timer, a waveform synthesis circuit, a power amplifier, a sequence control circuit and excitation coils. First, the wireless magnetic sensor measures the strength of the magnetic field produced by the magnetic generator. Via radio frequency communication, the measured result is feedback to the comparator of the microcontroller. According to a deviation obtained by comparing the measured results with the reference value, the microcontroller outputs a digital signal to the DA converter to control the magnitude of the exciting current. The prototype of the system was developed and the experiment was performed. The experiment shows that the magnetic field generator can automatically adjust the strength of the exciting signal.
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Sun, Jie, and Jianhui Wu. "A 12-bit 350 MS/s Single-Channel Pipeline ADC with 75 dB SFDR in 0.18 μm BiCMOS." Journal of Circuits, Systems and Computers 28, no. 03 (February 24, 2019): 1950044. http://dx.doi.org/10.1142/s0218126619500440.
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A 12-bit 350[Formula: see text]MS/s ADC with 75[Formula: see text]dB SFDR fabricated in 0.18[Formula: see text][Formula: see text]m SiGe BiCMOS process is presented. To improve the power efficiency, the ADC employs a novel residue amplifier (RA) by exploiting the hetero-junction bipolar transistor (HBT). We also propose a fast comparator to save time for the residue settling of pipeline stages. A fully integrated reference buffer with “negative bootstrap power” (NBP) is proposed to improve both high power supply rejection ratio (PSRR) and ground supply rejection ratio (GSRR). A bandgap reference (BGR) with ultra-low leakage current start-up loop is also presented. The measured results show that with Nyquist input, the SFDR achieves 75[Formula: see text]dB and 63[Formula: see text]dB SNDR up to 350[Formula: see text]MS/s and consumes 180[Formula: see text]mW (only ADC core) with 580[Formula: see text]fj/cov Waldon FOM.
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Hernández-Gómez, Cristhian, Elsa De La Cadena, Maria F. Mojica, Adriana Correa, Marcela Perengüez, Sergio Gutiérrez, Christian Pallares, Catalina López, Monica Maria. Rojas Rojas, and Maria Virginia Villegas. "1581. Comparative In Vitro Activity of Ceftolozane/tazobactam and Comparator Agents Against Enterobacteriaceae and Pseudomonas Aeruginosa Clinical Isolates in Colombia." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S577. http://dx.doi.org/10.1093/ofid/ofz360.1445.
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Abstract Background Multidrug-resistant Enterobacteriaceae (Ent) and Pseudomonas aeruginosa (Pae) are involved in a considerable number of healthcare-associated infections, thus representing a therapeutic challenge. Ceftolozane–tazobactam (C/T) is a combination of a novel cephalosporin with a known β-lactamase inhibitor. Ceftolozane has high affinity for penicillin-binding proteins, improved outer membrane permeability, increased stability against efflux and enhanced stability against chromosomal AmpC β-lactamases compared with other β-lactam antibiotics. This agent is not active against carbapenemases. We evaluated the in vitro activity of C/T against clinical isolates of Ent and Pae collected from 2016- 2017 and compared it to the activity of broad-spectrum antimicrobial agents. Methods 1.644 Ent and Pae non-duplicate clinical isolates were collected in 13 medical centers located in 12 Colombian cities. Minimum inhibitory concentrations (MIC) were performed by broth microdilution and interpreted according to current CLSI guidelines. Isolates tested included 813 Escherichia coli (Eco), 441 Klebsiella pneumoniae (Kpn), 82 Enterobacter spp., (Enb); 60 Serratia marcescens (Sma) and 248 Pae. Comparator agents were ceftriaxone (CRO), cefotaxime (CTX), ceftazidime (CAZ), cefepime (FEP), piperacillin/tazobactam (TZP), ertapenem (ETP), imipenem (IMI), meropenem (MEM). Results Susceptibilities to C/T and comparators of 4 Ent species and Pae are shown in Table 1. Compared with other β-lactams such as CRO, CAZ, TZP, and FEP, C/T had considerably higher susceptibility rates against ESBL, non-carbapenem-resistant (CR) Eco and Kpn isolates. C/T MIC50/90 were: Eco (≤1/≤1); Kpn (≤1/128); Enb (≤1/64); Sma (≤1/≥256); Pae (≤1/≥256). In the case of P.aeruginosa despite the high resistance rates observed in the study, C/T had the best susceptibility, even higher than the carbapenems. Conclusion Overall, C/T demonstrated higher in vitro activity than currently available cephalosporins and TZP when tested against Ent and Pae. C/T provides an important treatment option against infections caused by non-carbapenemase producing Gram-negative pathogens. Further studies are warranted to identify an emerging mechanism of resistance in Colombia. Disclosures All authors: No reported disclosures.
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Łaś, Patryk, and Piotr Wiśniowski. "Method of Step Detection and Counting Based on Measurements of Magnetic Field Variations." Sensors 21, no. 23 (November 23, 2021): 7775. http://dx.doi.org/10.3390/s21237775.
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Basic human activity recognition (HAR) and analysis is becoming a key aspect of tracking and identifying daily habits that can have a critical impact on healthy lifestyles by providing feedback on health status and warning of deterioration. However, current approaches for detecting basic activities such as movements or steps rely on solutions with multiple sensors which affect their size and power consumption. In this paper, we propose a novel method that uses only a single magnetic field sensor for basic step detection, unlike the well-known multisensory solutions. The approach presented here is based on real-time analysis of magnetic field sensor measurements to detect and count steps during a walking activity. The approach is implemented in a system that integrates a digital magnetic field sensor with software blocks: filter, steady state detector, extrema detector with classifier, and threshold comparator implemented in an embedded platform. Outdoor experiments with volunteers of different ages and genders walking at variable speeds showed that the proposed detection method achieves up to 98% accuracy in step detection. The obtained results show that a single magnetic field sensor can be used to detect steps, and in general offers the possibility of simplifying the current solutions by reducing the device dimensions, the cost of a system and its power consumption.
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Mir, Burhan, Pawel Niewczas, and Grzegorz Fusiek. "Design and Implementation of a Passive Autoranging Circuit for Hybrid FBG-PZT Photonic Current Transducer." Sensors 23, no. 1 (January 3, 2023): 551. http://dx.doi.org/10.3390/s23010551.
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In this paper, we present a novel technique for passively autoranging a photonic current transducer (PCT) that incorporates a current transformer (CT), piezoelectric transducer (PZT) and fiber Bragg grating (FBG). Due to the usage of single-mode fiber and FBG, multiple PCTs can be interconnected and distributed over a long distance, for example along a power network, greatly reducing the cost of sensor deployment and offering other unique advantages. The autoranging technique relies on the usage of multiple, serially connected CT burden resistors and associated static MOSFET switches to realize instantaneous shortening of the resistors in response to increasing measured current. This functionality is realized passively, utilizing a modular, μW-power comparator circuit that powers itself from the electrical energy supplied by the CT within a small fraction of the 50/60 Hz cycle. The resultant instantaneous changes in sensor gain will be ultimately detected by the central FBG interrogator through real-time analysis of the optical signals and will be used to apply appropriate gain scaling for each sensor. The technique will facilitate the usage of a single PCT to cover an extended dynamic range of the measurement that is required to realize a combined metering- and protection-class current sensor. This paper is limited to the description of the design process, construction, and testing of a prototype passive autoranging circuitry for integration with the PCT. The two-stage circuitry that is based on two burden resistors, 1 Ω and 10 Ω, is used to prove the concept and demonstrate the practically achievable circuit characteristics. It is shown that the circuit correctly reacts to input current threshold breaches of approximately 2 A and 20 A within a 3 ms reaction time. The circuit produces distinct voltage dips across burden resistors that will be used for signal scaling by the FBG interrogator.
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S. Salim, Ahmad, and Asmaa A. Abdalla. "The State-of-the-art Technique for Determining the Identity and Uniqueness of Common Color Laser Printouts by Coded Dot Matrix Patterns." Arab Journal of Forensic Sciences and Forensic Medicine 5, no. 1 (June 6, 2023): 58–73. http://dx.doi.org/10.26735/rugh9293.
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Recently, in forensic science studies, identification of the source of color laser printouts is one of the most challenging issues that hinder forensic document examiners. Although various methods for establishing the identity of the source of color laser printouts are currently available worldwide, none of those methods approaches an accuracy and precision of 100%. The coded dot matrix patterns are state-of-the-art prototypes of steganography based on the active technique. Upon tracking the coded dot matrix patterns of all investigated color laser printouts, the identity and uniqueness can be determined, respectively. In the current paper, nineteen variant brands of color laser printer machines were selected. The advanced security features embedded in their printouts have steganalysis and grouped them into two broad categories. A direct model of hyperspectral analysis integrated with video spectral comparator Regula® 4307 was applied. The complete identification of the investigated color laser printouts was achieved. The decisive degree of the results reached one hundred percent for the investigated color laser in this study. Moreover, the novel classification scheme of coded dot matrix patterns presents for completing the individual characteristics.
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Spira, Alexander I., Joanne Chiu, Chin Chou Wang, Alona Zer, John Conibear, Patrick Hoang Phuong, Joseph K. Park, Anna Seto, Jie Zhang, and Byoung Chul Cho. "VELOCITY-Lung: A phase (Ph) 2 study evaluating safety and efficacy of domvanalimab (dom) + zimberelimab (zim) + sacituzumab govitecan (SG), or etrumadenant (etruma) + dom + zim, or etruma + zim in patients (pts) with treatment-naïve metastatic non-small cell lung cancer (mNSCLC)." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): TPS9155. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.tps9155.
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TPS9155 Background: Current standard of care (SOC) for pts with mNSCLC lacking an actionable mutation includes checkpoint inhibitor (CPI), platinum (PT)-based therapy, or a combination of the two, but is associated with poor outcomes. SG is a Trop-2–directed antibody-drug conjugate. SG monotherapy resulted in a 17% objective response rate (ORR), with a manageable safety profile in pts with mNSCLC who had multiple prior therapies (Heist RS, et al. J Clin Oncol. 2017), and a Ph 2 study is currently ongoing assessing SG+CPI±PT-based therapy (NCT05186974) in treatment-naïve mNSCLC. Etruma (dual adenosine receptor antagonist), dom (anti-TIGIT), and zim (anti–PD-1) are under clinical investigation for antitumor activity. Substudy-01 is part of the VELOCITY-Lung Ph 2 platform study evaluating novel treatment combinations in pts with treatment-naïve mNSCLC. Methods: VELOCITY-Lung (NCT05633667) is an open-label, multicenter, randomized, Ph 2 platform study. Key eligibility criteria for substudy-01 include age ≥18 y; pathologically documented stage IV NSCLC at time of study entry without EGFR, ALK, or other actionable genomic alterations; no prior systemic treatment for mNSCLC; ECOG PS 0-1; any PD-L1 status. Pts previously treated in the (neo)adjuvant setting may be included if therapy was completed ≥12 mo before study drug initiation. Current treatment arms in the preliminary stage are Arm A: dom+zim+SG; Arm B: etruma+dom+zim; Arm C: etruma+zim. Dosing will be as follows: etruma 150 mg po once daily, dom 1200 mg IV q3wk, zim 360 mg IV q3wk, SG 10 mg/kg IV on D1 and D8 of a 21-D cycle. Randomization will be stratified by histology and baseline PD-L1 status (central testing; ≥50% vs < 50%). Pts are randomized equally between treatment arms (arms can be added to evaluate additional novel combinations) in the preliminary stage. Once the expansion stage opens, pts will be randomized based on the number of experimental arms in the expansion stage, the comparator arm, and any newly added preliminary stage treatment arms. Pts will continue to receive treatment until progressive disease, death, unacceptable toxicity, or initiation of a subsequent anticancer therapy. The primary endpoint is ORR assessed by investigator per RECIST v1.1. Secondary endpoints include progression-free survival, duration of response, overall survival, and safety. During the preliminary stage, efficacy will be compared with historical SOC; during the expansion stage, efficacy will be compared with an active comparator arm within the study. Depending on the number of arms being tested in the expansion stage, this study plans to enroll ~69 to 289 patients globally and is open for recruitment. Clinical trial information: NCT05633667 .
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Conlan, J., Anders Sjöstedt, H. Gelhaus, Perry Fleming, Kevan McRae, Ronald Cobb, Roberto De Pascalis, and Karen Elkins. "Modern Development and Production of a New Live Attenuated Bacterial Vaccine, SCHU S4 ΔclpB, to Prevent Tularemia." Pathogens 10, no. 7 (June 23, 2021): 795. http://dx.doi.org/10.3390/pathogens10070795.
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Inhalation of small numbers of Francisella tularensis subspecies tularensis (Ftt) in the form of small particle aerosols causes severe morbidity and mortality in people and many animal species. For this reason, Ftt was developed into a bona fide biological weapon by the USA, by the former USSR, and their respective allies during the previous century. Although such weapons were never deployed, the 9/11 attack quickly followed by the Amerithrax attack led the U.S. government to seek novel countermeasures against a select group of pathogens, including Ftt. Between 2005–2009, we pursued a novel live vaccine against Ftt by deleting putative virulence genes from a fully virulent strain of the pathogen, SCHU S4. These mutants were screened in a mouse model, in which the vaccine candidates were first administered intradermally (ID) to determine their degree of attenuation. Subsequently, mice that survived a high dose ID inoculation were challenged by aerosol or intranasally (IN) with virulent strains of Ftt. We used the current unlicensed live vaccine strain (LVS), first discovered over 70 years ago, as a comparator in the same model. After screening 60 mutants, we found only one, SCHU S4 ΔclpB, that outperformed LVS in the mouse ID vaccination-respiratory-challenge model. Currently, SCHU S4 ΔclpB has been manufactured under current good manufacturing practice conditions, and tested for safety and efficacy in mice, rats, and macaques. The steps necessary for advancing SCHU S4 ΔclpB to this late stage of development are detailed herein. These include developing a body of data supporting the attenuation of SCHU S4 ΔclpB to a degree sufficient for removal from the U.S. Select Agent list and for human use; optimizing SCHU S4 ΔclpB vaccine production, scale up, and long-term storage; and developing appropriate quality control testing approaches.
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Perera, Sue, Liyuan Ma, Raj Punwaney, and Sulabha Ramachandran. "Clinical and Cost Burden of Primary Sjögren’s Syndrome: Descriptive Analysis Using a US Administrative Claims Database." Journal of Health Economics and Outcomes Research 5, no. 2 (February 22, 2018): 150–61. http://dx.doi.org/10.36469/9807.
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Background: Current knowledge of the disease burden of primary Sjögren’s syndrome (pSS) is limited. Objectives: The primary objective of this study was to describe the demographic and clinical characteristics of patients with pSS. The secondary objective was to describe the treatment patterns and healthcare resource utilization of patients with pSS. Furthermore, clinical characteristics of interest were described and the proportions of patients with glandular versus extra-glandular disease were reported. Methods: This was a retrospective cohort study (HO-15-16077) conducted in the US Truven MarketScan Commercial database. We report descriptive data from employees and their families, as covered by employer-sponsored medical insurance. The primary cohort comprised patients with pSS (with ≥1 diagnosis of sicca syndrome prior to January 1, 2013), with continuous enrollment for ≥24 months (January 1, 2012–December 31, 2013). Patients with conditions mimicking sicca symptoms not due to SS were excluded, as were those with connective tissue disease that may have suggested secondary SS. To compare the healthcare burden of patients with and without sicca symptoms, a 1:1 matched comparator population comprising subjects without a previous diagnosis of sicca syndrome (sicca-free) was also identified. Results: There were 12 717 eligible patients in the primary cohort. The majority (86%) was female and the mean age was 51 years. Overall, 60.7% of patients had claims associated with pSS extra glandular disease manifestations. These patients experienced a higher disease burden, and more commonly reported pain, fatigue or insomnia and any combination of pain, fatigue or insomnia (41.3%) compared with patients with glandular disease only (12.4%). Patients in the primary cohort incurred greater annual healthcare service costs (1.6 times greater, all causes) and healthcare resource utilization compared with the sicca-free comparator cohort. Patients with extra glandular disease also incurred greater average annual costs (2.9 times) contributing to ≥2 times/year more resource use for outpatient services than patients with glandular disease only. Conclusion: Patients with pSS experience a high disease burden despite treatment. This study provides novel insights in to the extent of the burden on healthcare resources among patients with pSS, in particular for patients with extra-glandular disease manifestations, when compared with sicca-free subjects.
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Shinde, Vivek, Rongman Cai, Joyce S. Plested, Bin Zhou, Haixia Zhou, Mingzhu Zhu, Nan Wang, et al. "2753. Induction of Broadly Cross-Reactive Immune Responses Against A(H3N2) Airuses: Results of a Phase 2 Trial of a Novel Recombinant Hemagglutinin Saponin-Adjuvanted Nanoparticle Seasonal Influenza Vaccine." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S970. http://dx.doi.org/10.1093/ofid/ofz360.2430.
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Abstract Background We developed a recombinant saponin-adjuvanted (Matrix-M1) quadrivalent hemagglutinin nanoparticle influenza vaccine (qNIV; NanoFlu) for older adults to address two impediments to efficacy of current, predominantly egg-derived, seasonal influenza vaccines: (1) limited protection against antigenic drift variants, particularly H3N2 viruses; and (2) antigenic mismatch between vaccine and circulating strains due to egg-adaptive mutations arising during manufacturing. In a prior Phase 1 trial, we showed that qNIV induced robust, broadly cross-reactive antibody responses against multiple antigenically drifted H3N2 viruses, which were 47–64% better than the egg-derived comparator trivalent high-dose inactivated influenza vaccine (IIV3-HD; Fluzone-High Dose). We undertook a Phase 2 trial to optimize the formulation of qNIV, and to compare qNIV immune responses to those of IIV3-HD and quadrivalent recombinant influenza vaccine (RIV4; FluBlok). Methods In this phase 2 dose and formulation finding RCT, we randomized 1,375 subjects aged ≥65 years to be immunized with 1 of 7 test vaccines: 5 different formulations of qNIV, IIV3-HD, or RIV4; and assessed wild-type hemagglutinin-inhibition (wt-HAI) and microneutralization (wt-MN) antibody responses (Day 0/28/56). Results Matrix-M1-adjuvanted qNIV induced 15–29% higher wt-HAI titers across 5 vaccine homologous or drifted H3N2 strains at Day 28 relative to unadjuvanted qNIV (statistically significantly superior for 5 of 6 strains tested). At Day 28, several qNIV formulations induced significantly superior wt-HAI titers vs. IIV3-HD (39–45%, 17–22%, and 44–48% greater titers for homologous A/Singapore/INFIMH-16–0019/2016—H3N2, historic-drifted A/Switzerland/9715293/2013—H3N2, and forward-drifted A/Wisconsin/19/2017—H3N2, respectively); and comparable HAI titers vs. RIV4. Wt-MN and wt-HAI data showed concordant patterns across treatment groups. Conclusion qNIV induced superior wt-HAI antibody responses vs. IIV3-HD against homologous or drifted H3N2 viruses and similar responses to RIV4. qNIV may address several critical challenges confronting current egg-derived influenza vaccines, especially in the older adult population. Disclosures All authors: No reported disclosures.
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Träff, H. "Novel approach to high speed CMOS current comparators." Electronics Letters 28, no. 3 (1992): 310. http://dx.doi.org/10.1049/el:19920192.
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Jia, Hanbo, Xuan Guo, Xuqiang Zheng, Xiaodi Xu, Danyu Wu, Lei Zhou, Jin Wu, and Xinyu Liu. "A 4-bit 36 GS/s ADC with 18 GHz Analog Bandwidth in 40 nm CMOS Process." Electronics 9, no. 10 (October 20, 2020): 1733. http://dx.doi.org/10.3390/electronics9101733.
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This paper presents a 4-bit 36 GS/s analog-to-digital converter (ADC) employing eight time-interleaved (TI) flash sub-ADCs in 40 nm complementary metal-oxide-semiconductor (CMOS) process. A wideband front-end matching circuit based on a peaking inductor is designed to increase the analog input bandwidth to 18 GHz. A novel offset calibration that can achieve quick detection and accurate correction without affecting the speed of the comparator is proposed, guaranteeing the high-speed operation of the ADC. A clock distribution circuit based on CMOS and current mode logic (CML) is implemented in the proposed ADC, which not only maintains the speed and quality of the high-speed clock, but also reduces the overall power consumption. A timing mismatch calibration is integrated into the chip to achieve fast timing mismatch detection of the input signal which is bandlimited to the Nyquist frequency for the complete ADC system. The experimental results show that the differential nonlinearity (DNL) and integral nonlinearity (INL) are −0.28/+0.22 least significant bit (LSB) and −0.19/+0.16 LSB, respectively. The signal-to-noise-and-distortion ratio (SNDR) is above 22.5 dB and the spurious free dynamic range (SFDR) is better than 35 dB at 1.2 GHz. An SFDR above 24.5 dB and an SNDR above 18.6 dB across the entire Nyquist frequency can be achieved. With a die size of 2.96 mm * 1.8 mm, the ADC consumes 780 mW from the 0.9/1.2/1.8 V power supply.
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Robertson, Craig A., and Terence Gourlay. "Development of a diagnostic sensor for measuring blood cell concentrations during haemoconcentration." Perfusion 32, no. 2 (September 24, 2016): 126–32. http://dx.doi.org/10.1177/0267659116667806.
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Background: HemoSep® is a commercial ultrafiltration and haemoconcentration device for the concentration of residual bypass blood following surgery. This technology is capable of reducing blood loss in cardiac and other types of “clean site” procedures, including paediatric surgery. Clinical feedback suggested that the device would be enhanced by including a sensor technology capable of discerning the concentration level of the processed blood product. We sought to develop a novel sensor that can, using light absorption, give an accurate estimate of packed cell volume (PCV). Materials and methods: A sensor-housing unit was 3D printed and the factors influencing the sensor’s effectiveness – supply voltage, sensitivity and emitter intensity - were optimised. We developed a smart system, using comparator circuitry capable of visually informing the user when adequate PCV levels (⩾35%) are attained by HemoSep® blood processing, which ultimately indicates that the blood is ready for autotransfusion. Results: Our data demonstrated that the device was capable of identifying blood concentration at and beyond the 35% PCV level. The device was found to be 100% accurate at identifying concentration levels of 35% from a starting level of 20%. Discussion: The sensory capability was integrated into HemoSep’s® current device and is designed to enhance the user’s clinical experience and to optimise the benefits of HemoSep® therapy. The present study focused on laboratory studies using bovine blood. Further studies are now planned in the clinical setting to confirm the efficacy of the device.
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Castanheira, Mariana, Jill Lindley, Holly Huynh, Rodrigo E. Mendes, and Olga Lomovskaya. "690. Activity of a Novel Polymyxin Analog, QPX9003, Tested Against Resistant Gram-Negative Pathogens, Including Carbapenem-Resistant Acinetobacter, Enterobacterales, and Pseudomonas." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S313. http://dx.doi.org/10.1093/ofid/ofz360.758.
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Abstract Background Multidrug resistance (MDR) among Gram-negative (GN) organisms and the limited active therapeutic options against these pathogens are matters of worldwide concern. Polymyxins are cationic peptides that act on the bacterial cell membrane and have good activity against GN organisms, including MDR strains. We evaluated the activity of QPX9003, a novel polymyxin analog with an improved safety profile over current polymyxins, against a large collection of resistant GN isolates collected worldwide. Methods Susceptibility testing was performed by reference microbroth dilution against 2,518 GN organisms for QPX9003, colistin (COL), levofloxacin, tigecycline, gentamicin, amikacin, meropenem, cefepime, piperacillin–tazobactam, and ceftazidime–avibactam. Isolates included 1,000 Pseudomonas aeruginosa (PSA) enriched for MDR, 503 carbapenem-resistant Acinetobacter baumannii (CRAB), and 1,105 Enterobacterales (ENT). Results QPX9003 had potent activity against PSA isolates enriched for resistance against β-lactam/β-lactamase inhibitor combinations and was 4-fold more potent than COL (MIC50/90, 0.25/0.25 mg/L vs. MIC50/90 of 1/1 mg/L). QPX9003 was also more potent than COL against the panel of CRAB with MIC50/90 of 0.125/1 mg/L and 0.5/4 for QPX9003 and COL, respectively. QPX9003 had a modal MIC of 0.06 mg/L against a large collection of ENT isolates resistant to cephalosporins and/or carbapenems (MIC50/90, 0.06/16 mg/L). QPX9003 activity was identical against 508 carbapenem-resistant Enterobacterales (CRE; MIC50/90, 0.06/16 mg/L) isolates and 511 Klebsiella pneumoniae isolates (MIC50/90, 0.06/16 mg/L) in this collection. Escherichia coli isolates were considerably more sensitive to QPX9003 (MIC50/90, 0.06/0.12 mg/L) compared with K. pneumoniae isolates. Activity of QPX9003 and COL was similar against ENT. Other comparator agents had limited activity against PSA, CRAB, and CRE isolates. Conclusion QPX9003 had activity against this collection of highly resistant GN isolates and was particularly active against the PSA and CRAB isolates. QPX9003 is a promising new-generation polymyxin agent. Disclosures All authors: No reported disclosures.
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Dispirito, Joanna R., Mehmet G. Badur, Subhabrata 'Brad' Biswas, Diogo M. Camacho, Aditi Chalishazar, Brian DeChristopher, Katie Sellers, et al. "Allosteric Inhibition of MALT1 Is Efficacious in a Model of Chronic Graft-Versus-Host Disease and Modulates Immunometabolic Activation." Blood 138, Supplement 1 (November 5, 2021): 3810. http://dx.doi.org/10.1182/blood-2021-149762.
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Abstract Introduction Graft-versus-host disease (GVHD) is a severe complication of allogeneic hematopoietic cell transplantation. In its chronic form, GVHD causes prolonged post-transplant morbidity and significant mortality. There is a paucity of approved therapies and the current standard of care results in incomplete responses that leave significant unmet need for novel agents. Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a bi-functional protein that acts as a signal-propagation scaffold and protease for selective innate and adaptive immune cell receptor signaling. The established link between MALT1 and receptor-mediated activation of multiple immune cell types involved in cGVHD argues for it as a therapeutic target for cGVHD. Furthermore, we have identified MALT1 signaling to be important in linking receptor-initiated signaling to changes in cellular metabolism necessary for immune cell effector function and propose that immunometabolic profiling of immune cells from cGVHD patients may provide novel biomarkers of both disease pathophysiology and associated MALT1 activity. Methods, Results, Conclusion To assess MALT1 as a novel drug target in cGVHD, we first characterized the effectiveness of allosteric inhibition on protease, scaffolding, and metabolic activity in primary human T cells. MALT1 inhibition of T-cell receptor (TCR) activated CD4 + T cells reduced protease activity by >90% and scaffolding activity by ∼50%, downstream of TCR activation. Consistent with disruption of the TCR signaling cascade, MALT1 inhibition reduced T H1 and T H17 cytokines, and the T FH cytokine IL-21 in a concentration dependent manner. B-cell receptor (BCR) driven proliferation of human B cells and C-type-lectin receptor and immune complex driven cytokine production from human macrophages were also inhibited. We next tested MALT1 inhibition in a sclerodermatous rodent model of cGVHD (scGVHD). Allogeneic bone marrow and splenocytes from LP/J donor mice were transferred to irradiated C57BL/6 recipient mice. Starting on day 21 after transfer, animals were dosed orally once daily with a MALT1 inhibitor, or twice daily with the JAK1/2 inhibitor ruxolitinib as a comparator. All animals were monitored daily for weight change, survival and GVHD score. On a modified scGVHD scoring scale, animals treated with a MALT1 inhibitor had significantly more progression-free survival throughout the study than vehicle or ruxolitinib-treated animals. No differential effect was observed on body weight and overall survival. MALT1 inhibitor treatment, but not ruxolitinib, reduced frequencies of splenic T FH cells and germinal center B cells compared with vehicle-treated mice. Importantly, MALT1 inhibition had no effect on the frequency or numbers of splenic regulatory T cells. Additionally, a delayed-type hypersensitivity (DTH) response was abrogated with MALT1 inhibition, showing that T-cell-driven responses in the skin, an important target tissue in cGVHD, can be abrogated with MALT1 blockade. Given recent studies implicating MALT1 activity as a link between immunoreceptor signaling and activation-dependent metabolic activity in T cells, we performed non-targeted metabolomics on plasma and spleens from scGVHD animals. Clustering of splenic metabolite intensities across treatment groups revealed a subset of metabolites responsive to MALT1 inhibition. This motivated us to explore the metabolic activity of cells from GVHD patients. By developing a method to infer metabolic pathway activity from transcriptional profiles of whole blood, we were able to utilize publicly available RNA-seq data. Using a data set containing 8 healthy controls and longitudinal samples from 25 GVHD patients, this approach segregated GVHD patients into four subsets, with the two largest subsets showing oppositional activity in most major metabolic pathways. Collectively, these data reveal a breadth of MALT1 activity across diverse cell types implicated in the initiation and progression of cGVHD and support development of small-molecule inhibitors of MALT1. These data also define novel heterogeneity among GHVD patients based on immunometabolic activity and motivate development of metabolic biomarkers of MALT1 activity for clinical use. Figure 1 Figure 1. Disclosures Dispirito: Rheos Medicines: Current Employment. Badur: Rheos Medicines: Current Employment. Biswas: Rheos Medicines: Current Employment. Camacho: Rheos Medicines: Current Employment. Chalishazar: Rheos Medicines: Current Employment. DeChristopher: Rheos Medicines: Current Employment. Sellers: Rheos Medicines: Current Employment. Steadman: Rheos Medicines: Current Employment. Soh: Rheos Medicines: Current Employment. Monroe: Rheos Medicines: Consultancy. Long: Rheos Medicines: Current Employment.
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Ding, Ning, Yusong Mu, Yuping Guo, Teng Chen, and Yuchun Chang. "A 6.4-GS/s 10-b Time-Interleaved SAR ADC with Time-Skew Immune Sampling Network in 28-nm CMOS." Journal of Circuits, Systems and Computers 29, no. 16 (July 27, 2020): 2050264. http://dx.doi.org/10.1142/s0218126620502643.
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This paper presents a 6.4-GS/s 16-way 10-bit time-interleaved (TI) SAR ADC for wideband wireless applications. A two-stage master–slave hierarchical sampling network, which is immune to the time skew of multi-phase clocks, is introduced to avoid the time-skew calibration for design simplicity and hardware efficiency. To perform low distortion and fast sampling at acceptable power consumption, a linearity- and energy efficiency-improved track-and-hold (T&H) buffer with current-feedback compensation scheme is proposed. Accompanied by its low-output-impedance feature, the buffer obtains adequate bandwidth which can cover the entire ADC Nyquist sampling range. Moreover, the split capacitor DAC combined with a novel nonbinary algorithm is adopted in single-channel ADC, enabling a shorter DAC settling time as well as less switching energy. Capacitor mismatch effect with related design trade-off is discussed and behavior models are built to evaluate the effect of capacitor mismatch on ENOB. An asynchronous self-triggered SAR logic is designed and optimized to minimize the delay on logic paths to match up the acceleration on DAC and comparator. With these proposed techniques, the 10-b sub-ADC achieves a 400-MHz conversion rate with only 3.5-mW power consumption. The circuit is designed and simulated in TSMC 28 HPC process and the results show that the overall ADC achieves 54.6-dB SNDR and 58.1-dB SFDR at Nyquist input while consuming 127-mW power from 1-V/1.5-V supply and achieving a Walden FoM of 45[Formula: see text]fJ/conv-step.
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Seymour, Erlene K., Charles A. Schiffer, and Jonas A. de Souza. "Challenges in the Clinical Application of the American Society of Clinical Oncology Value Framework: A Medicare Cost-Benefit Analysis in Chronic Lymphocytic Leukemia." Journal of Oncology Practice 13, no. 12 (December 2017): e1002-e1011. http://dx.doi.org/10.1200/jop.2017.024778.
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Purpose: The ASCO Value Framework calculates the value of cancer therapies. Given costly novel therapeutics for chronic lymphocytic leukemia, we used the framework to compare net health benefit (NHB) and cost within Medicare of all regimens listed in the National Comprehensive Cancer Network (NCCN) guidelines. Methods: The current NCCN guidelines for chronic lymphocytic leukemia were reviewed. All referenced studies were screened, and only randomized controlled prospective trials were included. The revised ASCO Value Framework was used to calculate NHB. Medicare drug pricing was used to calculate the cost of therapies. Results: Forty-nine studies were screened. The following observations were made: only 10 studies (20%) could be evaluated; when comparing regimens studied against the same control arm, ranking NHB scores were comparable to their preference in guidelines; NHB scores varied depending on which variables were used, and there were no clinically validated thresholds for low or high values; treatment-related deaths were not weighted in the toxicity scores; and six of the 10 studies used less potent control arms, ranked as the least-preferred NCCN-recommended regimens. Conclusion: The ASCO Value Framework is an important initial step to quantify value of therapies. Essential limitations include the lack of clinically relevant validated thresholds for NHB scores and lack of incorporation of grade 5 toxicities/treatment-related mortality into its methodology. To optimize its application for clinical practice, we urge investigators/sponsors to incorporate and report the required variables to calculate the NHB of regimens and encourage trials with stronger comparator arms to properly quantify the relative value of therapies.
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Thyssen, Charlotte, Karel Deprez, Pieter Mollet, Roel Van Holen, and Stefaan Vandenberghe. "Simulation study on the performance of time-over-threshold based positioning in monolithic PET detectors." Physics in Medicine & Biology 66, no. 24 (December 21, 2021): 245025. http://dx.doi.org/10.1088/1361-6560/ac40d1.
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Abstract The vast majority of PET detectors in the field today are based on pixelated scintillators. Yet, the resolution of this type of detector is limited by the pixel size. To overcome this limitation, one can use monolithic detectors. However, this detector architecture demands specific and high-speed detector readout of the photodetector array. A commonly used approach is to integrate the current pulses generated by every pixel but such circuitry quickly becomes bulky, power consuming and expensive. The objective of this work is to investigate a novel readout and event positioning scheme for monolithic PET detectors, based on time-over-threshold (ToT). In this case, we measure the time that the pulse is above a certain threshold through a comparator. The pulse widths are used for event positioning using a mean nearest neighbour approach (mNN ToT ). For energy determination one integrating multiplexed channel is foreseen. We evaluate the positioning accuracy and uniformity of such a ToT detector by means of Monte Carlo simulations. The impact of the threshold value is investigated and the results are compared to a detector using mean nearest neighbour with pulse-integration (mNN int ), which has already proven to allow sub-mm resolution. We show minimal degradation in spatial resolution and bias performance compared to mNN int . The highest threshold results in the worst resolution performance but degradation remains below 0.1 mm. Bias is largely constant over different thresholds for mNN ToT and close to identical to mNN int . Furthermore we show that ToT performs well in terms of detector uniformity and that scattered photons can be positioned inside the crystal with high accuracy. We conclude from this work that ToT is a valuable alternative to pulse-integration for monolithic PET detectors. This novel approach has an impact on PET detector development since it has the advantage of lower power consumption, compactness and inherent amplitude-to-time conversion.
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Nicholson, Christopher J., Samuel J. Roth, Arudhir Singh, Caitlin Brown, Simon P. Fricker, Jon Hu, and Samantha Dale Strasse. "Abstract C052: Circumventing EGFR inhibitor resistance in NSCLC using transomics." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): C052. http://dx.doi.org/10.1158/1535-7163.targ-23-c052.
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Abstract Drug discovery continues to be refined to enhance efficiency, yet >80% of new drugs fail in the clinical trial stage. It is apparent that a novel approach is needed. COMPASS is a transomic analysis platform that integrates data across multiple omics layers; genomics, transcriptomics, proteomics, and phosphoproteomics. This analysis allows us to interpret complex biological relationships and provide a functional map of the biochemical drivers of disease. We have used EGFR inhibitor (EGFRi) resistance as a case study. EGFRi have been successful in treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (EGFRm), however, this success is temporary. The emergence of resistance is a problem and limits long-term treatment for many patients, even with osimertinib, a third-generation inhibitor and current standard of care. As resistance to EGFRi occurs through mutations in EGFR we adopted a novel strategy using COMPASS to identify and validate alternative, non-EGFR targets that could potentially recapitulate the pharmacological effects of EGFRi in EGFRm NSCLC. The transomic signatures of EGFRi were generated using a NSCLC cell line containing the activating mutation ex19del. The drug concentration required to inhibit cell growth (IC50) was first determined. For transomic analyses, cells were incubated for 24 h with the drug IC50 concentration and harvested for genomic, transcriptomic, proteomic, and phosphoproteomic analyses. We have previously shown transomics analysis can differentiate between EGFRi that have been designed to treat EGFRm NSCLC with the transomics signature for osimertinib being significantly different from comparator drugs that failed during drug development. We employed our proprietary target prioritization algorithm to further analyze the omics data to identify and rank novel targets. Targets were then filtered to select those with an available pharmacological tool compound (PTC). The PTCs were used to evaluate the targets in a xenograft model of osimertinib resistant NSCLC, PC9-Del19/T790M/C797S; which contains the activating EGFR mutation (ex19del), and two mutations conferring EGFRi resistance, T790M gatekeeper mutation, and C797S which confers resistance to osimertinib. Of the targets tested 82% (9/11) were associated with >25% inhibition of tumor growth. Furthermore, 36% (4/11) targets were associated with >50% inhibition by the PTCs, with inhibition of one target giving >85% inhibition resulting in stasis of tumor growth. Future work will investigate targets using gene silencing, as PTCs were not available for many of the novel high-ranked targets. These data show that using COMPASS transomic analysis, it is possible to identify novel drug targets to treat difficult-to-treat cancers such as EGFRi-resistant NSCLC and provides validation of this discovery platform by disease-relevant in vivo pharmacology. Further validation studies are ongoing against other difficult-to-treat cancers to identify novel clinical targets and drug candidates. Citation Format: Christopher J Nicholson, Samuel J Roth, Arudhir Singh, Caitlin Brown, Simon P Fricker, Jon Hu, Samantha Dale Strasse. Circumventing EGFR inhibitor resistance in NSCLC using transomics [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C052.
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Walenga, Jeanine M., Margaret Prechel, Walter P. Jeske, Meredith K. McDonald, James M. Daikur, and Wasimul Haque. "Novel Single Agents with Combined Anti-Coagulant and Anti-Platelet Activities: Potential Treatment Option for the Management of HIT." Blood 106, no. 11 (November 16, 2005): 1884. http://dx.doi.org/10.1182/blood.v106.11.1884.1884.
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Abstract A recently introduced series of antithrombotic agents brings the novel characteristic of dual anti-coagulant and anti-platelet actions in one molecule. These low molecular weight, synthetic, serine protease inhibitors, depending on structural modifications, have variable ratios of both anti-thrombin and anti-platelet activities. Studies have shown that these agents produce stronger antithrombotic actions relative to single targeted therapeutic agents (O. Iqbal #P0521 and D. Hoppensteadt #OR335, ISTH meeting Sydney, Australia August 2005). Heparin-induced thrombocytopenia (HIT) is an adverse effect of heparin in which both thrombin generation and platelet activation augment hypercoagulable and inflammatory states leading to a high probability of developing severe thrombosis. Current guidelines for patients who have HIT recommend the use of a direct thrombin inhibitor (DTI) to prevent or treat associated thrombosis. Clinical trial data, as well as practice outcomes, show that DTI treatment alone is not sufficient to overcome the pathology and resultant thrombosis in all HIT patients. Thus, more optimal treatment options are needed. A focus of treatment on inhibiting both platelet and coagulation activation is logical based on the pathophysiology of HIT. This study was undertaken to determine if the novel CanAm series of agents may have a role in the management of patients with HIT. Eight agents (MC45301, MC45308, CA207, CA216, CA234, CA247, CA250, CA254) with varying ratios of anticoagulant/anti-platelet activities were studied using the 14C-serotonin release assay (SRA) and flow cytometry for the detection of platelet P-selectin expression and platelet microparticle generation. The DTI argatroban, the FXa inhibitor fondaparinux, and the platelet GPIIb/IIIa receptor antagonist eptifibatide were included for comparison. Both cross-reactivity to HIT antibodies and amelioration of HIT antibody-induced platelet activation were assessed. In the absence of heparin, at 1-100 μg/ml none of the CanAm agents caused platelet activation in the presence of serum from patients with HIT (n=12) ruling out cross-reactivity with HIT antibodies. None of the comparator drugs showed cross reactivity with HIT antibodies. In the presence of heparin (0.1 U/ml) and serum from patients with HIT (n=12), the CanAm agents were able to inhibit all platelet activation responses at concentrations of 10–100 μg/ml. In comparison, the DTI and FXa inhibitor were not able to inhibit the HIT antibody/heparin induced platelet activation with any HIT serum. The GPIIb/IIIa inhibitor, however, showed a concentration-dependent inhibition of the platelet activities with complete blockade at 1 μg/ml, suggesting the importance of platelet activation inhibition for the treatment of HIT. Thus, compared to mono-therapeutic agents such as DTIs and fondaparinux, the dual-acting CanAm agents not only lack cross reactivity with HIT antibodies, but they have the added ability to block the antibody-induced platelet activation that occurs during an acute episode of HIT. A dual-acting anticoagulant/anti-platelet drug may, therefore, be of more value than single targeted anti-thrombin drugs for the management of HIT and associated thrombosis.
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Holyoke, Paul, Karthika Yogaratnam, and Elizabeth Kalles. "Web-Based Smartphone Algorithm for Calculating Blood Pressure From Photoplethysmography Remotely in a General Adult Population: Validation Study." Journal of Medical Internet Research 23, no. 4 (April 23, 2021): e19187. http://dx.doi.org/10.2196/19187.
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Background Outside of a clinical setting, oscillometric devices make remote monitoring of blood pressure and virtual care more convenient and feasible. HeartBeat Technologies Ltd developed a novel approach to measuring blood pressure remotely after an initial blood pressure reading by a nurse using the conventional measurement method. Using a finger pulse oximeter, a photoplethysmogram wave is transmitted by Bluetooth to a smartphone or tablet. A smartphone app (MediBeat) transmits the photoplethysmogram to a server for analysis by a proprietary algorithm—the person’s current blood pressure is sent back to the smartphone and to the individual’s health care provider. Objective This study sought to determine whether the HeartBeat algorithm calculates blood pressure as accurately as required by the European Society of Hypertension International Protocol revision 2010 (ESH-IP2) for validation of blood pressure measuring devices. Methods ESH-IP2 requirements, modified to conform to a more recent international consensus statement, were followed. The ESH-IP2 establishes strict guidelines for the conduct and reporting of any validation of any device to measure blood pressure, including using the standard manual blood pressure instrument as a comparator and specific required accuracy levels for low, medium, and high ranges of blood pressure readings. The consensus statement requires a greater number of study participants for each of the blood pressure ranges. The validation of the accuracy of the algorithm was conducted with a Contec CMS50EW pulse oximeter and a Samsung Galaxy XCover 4 smartphone. Results The differences between the HeartBeat-calculated and the manually measured blood pressures of 62 study participants did not meet the ESH-IP2 standards for accuracy for either systolic or diastolic blood pressure measurements. There was no discernible pattern in the inaccuracies of the HeartBeat-calculated measurements. Conclusions The October 4, 2019 version of the HeartBeat algorithm, implemented in combination with the MediBeat app, a pulse oximeter, and an Android smartphone, was not sufficiently accurate for use in a general adult population. Trial Registration ClinicalTrials.gov NCT04082819; http://clinicaltrials.gov/ct2/show/NCT04082819
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Fazeli, Mir Sohail, Divya Pushkarna, Ana Howarth, Margaret Hux, Mir-Masoud Pourrahmat, and Clara Chen. "Indirect Costs of Oral Versus Non-Oral Therapies in Hematologic Malignancies: A Systematic Literature Review." Blood 136, Supplement 1 (November 5, 2020): 30–31. http://dx.doi.org/10.1182/blood-2020-136773.
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Introduction: The treatment landscape for hematologic malignancies is evolving rapidly, and a range of therapeutic options with differing routes of administration is now available. The shifting dynamics of these novel therapies and increasing total treatment costs highlight the importance of value-based healthcare decisions that take patient, payer, and societal perspectives into account. It is therefore increasingly important to consider both direct and indirect costs when evaluating therapeutic options. Reducing healthcare visits for administration of non-oral therapies (injectable and/or mixed therapies) results in indirect cost savings and is of particular relevance during the current coronavirus disease (COVID-19) pandemic where there are distinct challenges with respect to visiting hospital settings. However, the indirect cost savings of utilizing oral versus non-oral treatments have yet to be fully assessed from a patient and societal perspective. The objective of this review was to assess the differences in indirect non-treatment-related costs between oral and non-oral therapies for hematologic malignancies. Methods: A systematic literature review (SLR) was conducted by searching the Embase®, MEDLINE®, EconLit, and Health Technology Assessment/National Health Service economic evaluation (HTA/NHS EED) databases from inception to June 2020. Additionally, literature searches of proceedings from the 2018-2020 American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), and The Professional Society for Health Economics and Outcomes Research (ISPOR) conferences were performed to capture recent studies not indexed in the main databases. A manual search of the reference list from all included study publications was also performed. Eligibility criteria for study identification were developed using the Population, Intervention, Comparator, and Outcome (PICO) framework. Eligible studies included cost models and observational studies reporting indirect costs from a patient and/or societal perspective for oral versus non-oral therapies. Results: A total of 4,012 records were identified by the searches. Following title/abstract screening, the full text of 25 publications was reviewed, and 5 studies conducted in the USA (n = 3), Italy (n = 1), and Finland (n = 1) were identified as eligible and selected for qualitative evidence synthesis (Table). Although the SLR protocol included all hematologic malignancies, only studies including patients with multiple myeloma (MM) were identified. The indirect costs reported across the selected studies varied and included costs such as loss of productivity, transportation, and patient and/or caregiver time. Among all 5 studies, total indirect costs for patients with MM were lower for oral versus non-oral regimens. In the USA-based studies, indirect costs were USD 70-1,202 per month for oral regimens versus USD 432-1,526 per month for non-oral regimens. In Europe-based studies, indirect cost estimates were EUR 1,800 versus EUR 17,000 per year for oral versus non-oral regimens (Italian study), and EUR 114 versus EUR 358 per 28-day cycle for oral versus non-oral regimens (Finnish study; averages calculated from ranges in Table). Conclusions: This SLR demonstrates a paucity of data on the indirect costs to patients and society of oral versus non-oral therapies for hematologic malignancies. The studies included in this review assessed differing types of indirect costs, including loss of productivity, transportation costs, and patient and/or caregiver time; however, all indicated that the administration of oral regimens is associated with lower indirect costs compared with non-oral regimens. This finding is compelling given the current global health crisis due to COVID-19, where prioritizing the concept of "value" means assessing more complex issues, such as indirect costs that may have a meaningful impact on patients and society. Disclosures Fazeli: Evidinno Outcomes Research Inc.: Current Employment. Pushkarna:Evidinno Outcomes Research Inc.: Current Employment. Howarth:Evidinno Outcomes Research Inc.: Current Employment. Hux:Evidinno Outcomes Research Inc.: Consultancy. Pourrahmat:Evidinno Outcomes Research Inc.: Current Employment. Chen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.
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Kaiser, Martin F., Andrew Hall, Katrina Walker, Nicola Newnham, Ruth M. de Tute, Sadie Roberts, Emma Ingleson, et al. "Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, Dexamethasone (Dara-CVRd), V-Augmented Autologous Stem Cell Transplant (V-ASCT) and Dara-Vrd Consolidation in Ultra-High Risk (UHiR) Newly Diagnosed Myeloma (NDMM) and Primary Plasma Cell Leukemia (pPCL) Compared with Myeloma XI/XI+ Trial Treatment for Uhir MM: The UK Optimum/Muknine Trial." Blood 138, Supplement 1 (November 5, 2021): 465. http://dx.doi.org/10.1182/blood-2021-144990.
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Abstract Background: Outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with primary plasma cell leukemia (pPCL) remain unsatisfactory with current standard therapies. Traditional comparative trials randomising against a standard of care control arm are thus challenging for patients with UHiR NDMM or pPCL, and novel approaches to address their high unmet need are required. OPTIMUM/MUKnine (NCT03188172) is a 'digital comparator arm' trial for UHiR NDMM and pPCL patients with protocol defined outcome comparison against fully molecularly matched UHiR patients from the near-concurrent NCRI Myeloma XI/XI+ trial, the 'MyXI prior'. We report final analysis of the primary endpoint progression free survival (PFS) at 18 months for patients treated in OPTIMUM with Dara-CVRd induction, V-augmented ASCT and Dara-VRd consolidation, compared to the MyXI prior. Methods: Between Sep 2017 and Jul 2019, 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened. 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts >20%) were identified and recruited to OPTIMUM. Patients received up to 6 cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 for 6 cycles (Cons1), Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression. This is the final analysis of the primary trial endpoint progression-free survival (PFS) at 18 months comparing OPTIMUM with the MyXI prior of patients treated with CRd or carfilzomib-CRd (KCRd) induction, ASCT and R maintenance or observation, using a Bayesian framework. Secondary endpoints include PFS, OS, safety and quality of life. Results: At median follow-up of 27.1 months (95% CI 25.1-29.3), median PFS was not reached for OPTIMUM patients. PFS was superior at the pre-specified time point of 18 months for OPTIMUM patients with an estimate of 81.7% (95% CI: 74.2-89.1) versus 65.9% (95% CI: 57.3-74.4) for the MyXI prior (Figure 1). PFS at 18 months was consistently shorter for both CRd (64.5%; 95% CI: 53.8-75.3) and KCRd (68.3%; 95% CI: 54.0-82.5) treated patients compared with OPTIMUM. There was a 99.5% chance of superior PFS outcome with OPTIMUM therapy compared to the MyXI prior within the Bayesian framework; easily surpassing the 85% pre-specified threshold of sufficient evidence of activity. The difference between trial treatments increased over time: 6 month estimates were similar across all treatment arms with OPTIMUM 95.3% (95% CI: 91.3-99.3), MyXI KCRd 95.1% (95% CI: 88.5-100.0), MyXI CRd 93.5% (95% CI: 88.0-99.0), while 12 month estimates were similar for OPTIMUM with 87.5% (95% CI: 81.2-93.9) and MyXI KCRd 87.8% (77.8-97.8), but lower in CRd 81.7% (95% CI: 73.0-90.3). The majority (94%) of patients who started OPTIMUM Cons1 completed all 6 cycles of therapy. Most frequent grade 3/4 adverse events (AEs) during Cons1 included thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%), however, grade 4 events were rare (<5%) for all categories, consistent with previously presented data on induction. We previously reported high MRD-negativity rates of 61% at day +100 post V-ASCT for OPTIMUM, with a lower rate of 40% of patients showing both complete response (CR) and MRD-neg. With further follow-up, CR rate increased to 68.2% (95% CI: 58.5-76.9) at end of Cons1, including virtually all patients with MRD-neg finding post V-ASCT. Conclusions: OPTIMUM demonstrated a clear PFS benefit at 18 months for intensified Dara combination therapy pre- and post-ASCT for UHiR NDMM and pPCL over the MyXI prior. Improvement of comparative benefit over time suggests particular efficacy of Dara-VRd in maintaining responses post ASCT, a key challenge in UHiR MM. This is, to our knowledge, the first prospective digital comparator trial for MM; central screening of an all-comer population combined with robust, detailed molecular matching maintained reliability and limited biases. These results demonstrate a novel framework for accelerated comparative evidence generation for patients with high unmet clinical need. Figure 1 Figure 1. Disclosures Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy. Hall: Janssen: Research Funding; BMS/Celgene: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Pratt: Binding Site: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy.