FPGA-Based Processor for Continual Capacitive-Coupling Impedance Spectroscopy and Circuit Parameter Estimation.

In principle, the recently proposed capacitive-coupling impedance spectroscopy (CIS) has the capability to acquire frequency spectra of complex electrical impedance sequentially on a millisecond timescale. Even when the measured object with time-varying unknown resistance Rx is capacitively coupled with the measurement electrodes with time-varying unknown capacitance Cx, CIS can be measured. As a proof of concept, this study aimed to develop a prototype that implemented the novel algorithm of CIS and circuit parameter estimation to verify whether the frequency spectra and circuit parameters could be obtained in milliseconds and whether time-varying impedance could be measured. This study proposes a dedicated processor that was implemented as field-programmable gate arrays to perform CIS, estimate Rx and Cx, and their digital-to-analog conversions at a certain time, and to repeat them continually. The proposed processor executed the entire sequence in the order of milliseconds. Combined with a front-end nonsinusoidal oscillator and interfacing circuits, the processor estimated the fixed Rx and fixed Cx with reasonable accuracy. Additionally, the combined system with the processor succeeded in detecting a quick optical response in the resistance of the cadmium sulfide (CdS) photocell connected in series with a capacitor, and in reading out their resistance and capacitance independently as voltages in real-time.

Short-Time Impedance Spectroscopy Using a Mode-Switching Nonsinusoidal Oscillator: Applicability to Biological Tissues and Continuous Measurement.

Herein, we propose an impedance spectroscopy method using a mode-switching nonsinusoidal oscillator and apply this method for measuring the impedance of biological tissues and continuous impedance measurement. To obtain impedance spectra over a wide frequency range, we fabricated a novel nonsinusoidal oscillator incorporating binary counters and analog switches. This oscillator could periodically switch oscillation frequency through the mode switching of the feedback resistor. From the oscillation waveform at each oscillation frequency of this circuit (oscillator), we determined the impedance spectrum of a measured object using the discrete-time Fourier transform. Subsequently, we obtained the broad impedance spectrum of the measured object by merging odd-order harmonic spectral components up to the 19th order for each oscillation frequency. From the measured spectrum, the resistive and capacitive components of the circuit simulating bioimpedance were estimated with high accuracy. Moreover, the proposed method was used to measure the impedance of porcine myocardium; changes in the impedance spectrum of the myocardial tissue due to coagulation could be measured. Furthermore, rapid variations in the resistance value of a CdS photocell could be continuously measured using the proposed method.

Non-Contact Measurements of Electrocardiogram and Cough-Associated Electromyogram from the Neck Using In-Pillow Common Cloth Electrodes: A Proof-of-Concept Study.

Asthma and chronic obstructive pulmonary disease are associated with nocturnal cough and changes in heart rate. In this work, the authors propose a proof-of-concept non-contact system for performing capacitive electrocardiogram (cECG) and cough-associated capacitive electromyogram (cEMG) measurements using cloth electrodes under a pillowcase. Two electrodes were located along with the approximate vector of lead II ECG and were used for both cECG and cEMG measurements. A signature voltage follower was introduced after each electrode to detect biopotentials with amplitudes of approximately 100 µV. A bootstrapping technique and nonlinear electrical component were combined and implemented in the voltage follower to attain a high input impedance and rapid static discharge. The measurement system was evaluated in a laboratory experiment for seven adult males and one female (average age: 22.5 ± 1.3 yr). The accuracy of R-wave detection for 2-min resting periods was 100% in six subjects, with an overall average of 87.5% ± 30.0%. Clearly visible cEMGs were obtained for each cough motion for all subjects, synchronized with reference EMGs from submental muscle. Although there remains room for improvement in practical use, the proposed system is promising for unobtrusive detection of heart rate and cough over a prolonged period of time.

Capacitive-Coupling Impedance Spectroscopy Using a Non-Sinusoidal Oscillator and Discrete-Time Fourier Transform: An Introductory Study.

In this study, we propose a new short-time impedance spectroscopy method with the following three features: (1) A frequency spectrum of complex impedance for the measured object can be obtained even when the measuring electrodes are capacitively coupled with the object and the precise capacitance of the coupling is unknown; (2) the spectrum can be obtained from only one cycle of the non-sinusoidal oscillation waveform without sweeping the oscillation frequency; and (3) a front-end measuring circuit can be built, simply and cheaply, without the need for a digital-to-analog (D-A) converter to synthesize elaborate waveforms comprising multiple frequencies. We built the measurement circuit using the proposed method and then measured the complex impedance spectra of 18 resistive elements connected in series with one of three respective capacitive couplings. With this method, each element's resistance and each coupling's capacitance were estimated independently and compared with their nominal values. When the coupling capacitance was set to 10 nF or 1.0 nF, estimated errors for the resistive elements in the range of 2.0-10.0 kΩ were less than 5%.

A Novel Analog Front End with Voltage-Dependent Input Impedance and Bandpass Amplification for Capacitive Biopotential Measurements.

This paper proposes a novel analogue front end (AFE) that has three features: voltage-dependent input impedance, bandpass amplification, and stray capacitance reduction. With a view to applying the AFE to capacitive biopotential measurements (CBMs), the three features were investigated separately in a schematic and mathematical manner. Capacitive electrocardiogram (cECG) or capacitive electromyogram (cEMG) measurements using the AFE were performed in low-humidity conditions (below 35% relative humidity) for a total of seven human subjects. Performance evaluation of the AFE revealed the following: (1) the proposed AFE in cECG measurement with 1.70-mm thick clothing reduced the baseline recovery time and root mean square voltage of respiratory interference in subjects with healthy-weight body mass index (BMI), and increased R-wave amplitude for overweight-BMI subjects; and (2) the proposed AFE in cEMG measurement of biceps brachii muscle yielded stable electromyographic waveforms without the marked DC component for all subjects and a significant (p < 0.01) increase in the signal-to-noise ratio. These results indicate that the proposed AFE can provide a feasible balance between sensitivity and stability in CBMs, and it could be a versatile replacement for the conventional voltage follower used in CBMs.

Development of a compact wireless Laplacian electrode module for electromyograms and its human interface applications.

In this study, we developed a compact wireless Laplacian electrode module for electromyograms (EMGs). One of the advantages of the Laplacian electrode configuration is that EMGs obtained with it are expected to be sensitive to the firing of the muscle directly beneath the measurement site. The performance of the developed electrode module was investigated in two human interface applications: character-input interface and detection of finger movement during finger Braille typing. In the former application, the electrode module was combined with an EMG-mouse click converter circuit. In the latter, four electrode modules were used for detection of finger movements during finger Braille typing. Investigation on the character-input interface indicated that characters could be input stably by contraction of (a) the masseter, (b) trapezius, (c) anterior tibialis and (d) flexor carpi ulnaris muscles. This wide applicability is desirable when the interface is applied to persons with physical disabilities because the disability differs one to another. The investigation also demonstrated that the electrode module can work properly without any skin preparation. Finger movement detection experiments showed that each finger movement was more clearly detectable when comparing to EMGs recorded with conventional electrodes, suggesting that the Laplacian electrode module is more suitable for detecting the timing of finger movement during typing. This could be because the Laplacian configuration enables us to record EMGs just beneath the electrode. These results demonstrate the advantages of the Laplacian electrode module.

Comparing integrated continuous process "LaVortex®" and conventional batch processes for the pharmaceutical manufacturing of acetaminophen oral dosage formulations: Challenges and pharmaceutical properties of the granular and tableted products.

LaVortex® was developed as a novel free-flow continuous granulation/drying (CGD) system. In this study, we compared the advantages and disadvantages of granules prepared by continuous and batchwise manufacturing systems. Granules containing 30 % acetaminophen were manufactured under various operating conditions using CGD system, with comparison granules manufactured using conventional batch systems that involve a combination of fluid bed granulation (FG), agitation granulation (AG), continuous drying, fluid bed drying, and/or shelf drying, after which the pharmaceutical properties of each type of manufactured granule were evaluated. Cumulative particle-size distributions were determined by sieving, powder flowabilities were determined by angle of repose measurements, and scanning electron microscopy was employed to examine granule morphologies. The CGD system produced fine-to-large spherical or ellipsoidal granules that exhibited excellent powder fluidities and tabletabilities that are almost identical to those of AG granules. Moreover, the CGD granules exhibited better powder flowability than the FG granules. The addition of water promoted CGD-granule growth and improved significantly powder flowability, and did a little in tabletability. Small spherical granules with good fluidity suitable for fine-particle-coating core materials, or large granules with excellent fluidity and tabletability, were prepared by adjusting the values of the elemental parameters of the CGD process.

Real-Time Monitoring of Critical Quality Attributes during High-Shear Wet Granulation Process by Near-Infrared Spectroscopy Effect of Water Addition and Stirring Speed on Pharmaceutical Properties of the Granules.

To produce high-quality pharmaceuticals, a real-time monitoring method for the high-shear wet granulation process (HSWG) was developed based on near-infrared spectroscopy (NIRS). Samples consisting of lactose, potato starch, and hydroxypropyl cellulose were prepared using HSWG with varying amounts of purified water (80, 90, and 100 mL) and impeller speed (200, 400, and 600 rpm), which produces granules of different characteristics. Twelve batches of samples were used for the calibration and nine batches were used for validation. After drying, the median particle size (D50), tapped density (TD), and Hauser ratio (HR) were measured. The best calibration models to predict moisture content (MC), D50, TD, and HR were determined based on pretreated NIR spectra using partial least squares regression analysis (PLSR). The temporal changes in the pharmaceutical properties under different amounts of water added and stirring speed were monitored in real time using NIRS/PLSR. Because the most important critical quality attribute (CQA) in the process was MC, granule characteristics such as D50, TD, and HR were analyzed with respect to MC. They might be used as robust and simple monitoring methods based on MC to evaluate the pharmaceutical properties of HSWG granules.

Changes in the Comprehensiveness of Rural Medical Care for Older Japanese Patients during the COVID-19 Pandemic.

Help-seeking behaviors (HSBs) refer to how people use lay and medical care to address their symptoms and diseases. The COVID-19 pandemic may have changed older, rural patients' preferences and experiences regarding HSBs, thereby, affecting the comprehensiveness of medical support for communities. This study identified changes in the comprehensiveness of medical care for older, rural patients, who are often dependent on others for accessing medical services. This observational study was performed with patients who lived in Unnan City. Patients' dependency and changes in comprehensiveness of medical services were assessed and calculated. The total usage of medical care decreased from 2018 to 2020 at all medical care levels. The proportion of patients who received comprehensive care was higher in 2020 than in 2018, at all care levels. At care dependent levels 3 to 5, the differences in the proportions were statistically significant. This study illustrates an association between the COVID-19 pandemic and the proportion of comprehensiveness of medical care among older rural patients with a decrease in medical care usage. Moreover, an improved proportion of comprehensiveness of medical care leads to appropriate HSBs. Going forward, HSBs and patient-centered care should be promoted by policy makers.

Comprehensive Care through Family Medicine: Improving the Sustainability of Aging Societies.

Comprehensive care through family medicine can enhance the approach to multimorbidity, interprofessional collaboration, and community care, and make medical care more sustainable for older people. This study investigated the effect of implementing family medicine and the comprehensiveness of medical care in one of the most rural communities. This implementation research used medical care data from April 2015 to March 2020. Patients' diagnoses were categorized according to the 10th revision of the International Statistical Classification of Disease and Related Health Problems (ICD-10). In 2016, family medicine was implemented in only one general hospital in Unnan. The comprehensiveness rate improved in all ICD-10 disease categories during the study period, especially in the following categories-infections; neoplasms; endocrine, nutritional, and metabolic diseases; mental disorders; nervous system; circulatory system; respiratory system; digestive system; skin and subcutaneous tissue; musculoskeletal system and connective tissue; and the genitourinary system. Implementing family medicine in rural Japanese communities can improve the comprehensiveness of medical care and resolve the issue of fragmentation of care by improving interprofessional collaboration and community care. It can be a solution for the aging of both patient and healthcare professionals. Future research can investigate the relationship between family medicine and patient health outcomes for improved healthcare sustainability.

Simultaneous Measurements of Capacitive Electrocardiogram and Ballistocardiogram Using In-Bed Fabric Sheet Electrode for Blood Pressure Estimation.

We recently reported the possibility of the simultaneous measurement of capacitive electrocardiogram (cEGC) and capacitive ballistocardiogram (cBCG) using non-contact capacitive coupling systems in bed. However, the relations of the two measurements with blood pressure (BP) have not been elucidated and cBCG measurements were unstable. Therefore, in this study, we improved the electrode and circuit, and succeeded in stable simultaneous measurement of cECG and cBCG. Synchronous averaging was performed to confirm the similarity of the waveform to the reproducibility of cBCG. Valsalva test (VT) was performed on seven subjects, and four verification intervals were set after VT. Then, the estimated blood pressure value was calculated using the instantaneous heart rate as the time difference parameter. We examined the relationship between estimated systolic blood pressure (eSBP) and systolic blood pressure (SBP) and observed a high positive correlation. cBCG contains components that are strongly related to BP. In the future, the electrode will be improved to measure cBCG at two points simultaneously at regular intervals to avoid shifting the Pulse Beat Arrival Time (PBAT) time axis. Further, in order to enhance the accuracy of blood pressure estimation, a change in the respiratory phase is incorporated into the estimation of the blood pressure value.

Non-contact Measurements of Blink-Associated Electrooculogram Using In-Pillow Cloth Electrodes: Potential Application as a Communication Aid.

Paralysis patients, particularly those with amyotrophic lateral sclerosis (ALS), gradually lose the ability to speak because of muscle loss. Even communication through gestures becomes difficult as their condition progresses. Eventually, the only means of communication left is eye movement. Using electrooculogram (EOG) signals, it is possible to improve the communication abilities of those patients who can move their eyes. We examined whether blinking could be detected from the back of the head in a noncontact manner using an in-pillow cloth electrode. We conducted an experiment aimed at detecting blinks in five subjects. The results revealed the possibility of measuring the change of potential related to blinks, with average sensitivity of 96%. This suggested the possibility of establishing a simple tool for ALS patients and paralysis patients to communicate through blinking.

Measurement of Vagus Nerve Response to Transcutaneous Electrical Ear Canal Stimulation in Anesthetized Rat.

Vagus nerve stimulation (VNS) administered to individuals following events such as severe trauma can be a potential therapy to attenuate gut injury and its sequelae. To determine the effective dose of transcutaneous electrical VNS (TE-VNS) and explore an effective method for performing TE-VNS, a measurement system was developed for the detection of vagus nerve response to TE-VNS. In addition, a noise-suppressed transcutaneous electrical stimulator (TES) was constructed for the same purpose. Using these tools, waveforms considered as nerve action potentials were successfully recorded. The recorded waveforms were similar to those evoked by direct electrical stimulation as reported in a latest publication. Our recorded waveforms also varied according to the pulse width of electrical stimulation, indicating the future possibility of determining the potential TES dose.Clinical Relevance- This is a basic research for application to acute therapy of systemic inflammatory response syndrome (SIRS) by transcutaneous electrical stimulation of the vagus nerve.

Electrical stimulation of the vagus nerve improves intestinal blood flow after trauma and hemorrhagic shock.

BACKGROUND: Gut damage after trauma/hemorrhagic shock contributes to multiple organ dysfunction syndrome. Electrical vagal nerve stimulation is known to prevent gut damage in animal models of trauma/hemorrhagic shock by altering the gut inflammatory response; however, the effect of vagal nerve stimulation on intestinal blood flow, which is an essential function of the vagus nerve, is unknown. This study aimed to determine whether vagal nerve stimulation influences the abdominal vagus nerve activity, intestinal blood flow, gut injury, and the levels of autonomic neuropeptides. METHODS: Male Sprague Dawley rats were anesthetized, and the cervical and abdominal vagus nerves were exposed. One pair of bipolar electrodes was attached to the cervical vagus nerve to stimulate it; another pair of bipolar electrodes were attached to the abdominal vagus nerve to measure action potentials. The rats underwent trauma/hemorrhagic shock (with maintenance of mean arterial pressure of 25 mmHg for 30 min) without fluid resuscitation and received cervical vagal nerve stimulation post-injury. A separate cohort of animals were subjected to transection of the abdominal vagus nerve (vagotomy) just before the start of cervical vagal nerve stimulation. Intestinal blood flow was measured by laser Doppler flowmetry. Gut injury and noradrenaline level in the portal venous plasma were also assessed. RESULTS: Vagal nerve stimulation evoked action potentials in the abdominal vagus nerve and caused a 2-fold increase in intestinal blood flow compared to the shock phase (P < .05). Abdominal vagotomy eliminated the effect of vagal nerve stimulation on intestinal blood flow (P < .05). Vagal nerve stimulation protected against trauma/hemorrhagic shock -induced gut injury (P < .05), and circulating noradrenaline levels were decreased after vagal nerve stimulation (P < .05). CONCLUSION: Cervical vagal nerve stimulation evoked abdominal vagal nerve activity and relieved the trauma/hemorrhagic shock-induced impairment in intestinal blood flow by modulating the vasoconstriction effect of noradrenaline, which provides new insight into the protective effect of vagal nerve stimulation.

L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer.

To find reliable biomarkers for high-grade malignancy, the relationship between immunohistochemical L-type amino-acid transporter 1 (LAT1) expression of biopsy samples, determined with the newly developed monoclonal antibody against human LAT1, and prognosis of patients with prostate cancer, was investigated. The intensity and score of immunohistochemical LAT1 expression of first biopsy samples were assessed using the modified Sinicrope et al. method and were found to be correlated with poor survival for the study group of 114 surgically treated patients as a whole (P = 0.0002 and 0.0270, respectively). LAT1 intensity further had a significant relationship (P = 0.0057) with prognosis in pathological T3 + T4 groups. Multivariate analysis indicated that the LAT1 intensity and score were more reliable prognostic markers, compared with the Gleason score and the Ki-67 labeling index. A relationship of the LAT1 intensity and score with prognosis could also be confirmed in 63 patients with inoperable cancer (P = 0.0070 and <0.0001, respectively). Similarly, significant differences in prognosis were confirmed in clinical T3 + T4 groups (P = 0.0091 and 0.0244, respectively). Moreover, the combination of LAT1 expression and Gleason score was found to have a more reliable correlation with prognosis. Thus, elevated LAT1 expression in prostate cancers is a novel independent biomarker of high-grade malignancy, which can be utilized together with the Gleason score, which is mainly dependent on cellular and structural atypia, to assess prognosis.

Noncontact In-Bed Measurements of Physiological and Behavioral Signals Using an Integrated Fabric-Sheet Sensing Scheme.

Home monitoring requires measuring the physiological and behavioral signals without impairing a subject's everyday life. This paper presents an integrated and noncontact approach for obtaining simultaneous physiological and behavioral signals of recumbent humans in beds using a home-monitoring application. In the proposed approach, a fabric-sheet unified sensing electrode (FUSE) obtains physiological signals by recording the electrocardiogram (ECG), chest and abdominal respiratory movements (RMs), and ballistocardiogram (BCG). The FUSE also detects the behavioral signals of body proximity (BPx) and lateral/supine lying postures. A prototype system with FUSE was validated in a short-term experiment and 6-h overnight measurements on two different groups composed of seven lying subjects. The results confirmed that the approach senses each signal independently and records the ECG, RMs, BCG, and BPx signals simultaneously. The mean sensitivities of the R and T waves of the ECG during sleep were 86.1% and 88.0%, respectively, whereas those of the chest and abdominal RMs were 90.7% and 90.1%, respectively. Although our prototype system has room for improvement, the results suggest that our approach enables the unconstrained, nocturnal monitoring of the physiological and behavioral signals in recumbent humans. The at-home monitoring of the physiological and behavioral signals is expected to contribute to cost-effective personalized healthcare in the future. This noncontact and easy-to-install system for in-bed measurements can facilitate a new era of home monitoring.

Non-Contact Capacitive Ballistocardiogram Measurements Using In-Bed Fabric-Sheet Electrode for Blood Pressure Estimation.

We recently reported the possibility of the simultaneous measurement of capacitive electrocardiogram (cEGC) and capacitive ballistocardiogram (cBCG) using non-contact capacitive coupling systems in bed. However, the relations of the two measurements with blood pressure (BP) have not been elucidated and cBCG measurements were unstable. Therefore, in this study, electrodes and systems for cEGC measurements were excluded, concerning the potential influence of interference. Electrode size was changed to stabilize cBCG measurements. The Valsalva test (VT) was performed on five subjects, and the correlations with BP were determined. A synchronous averaging process was performed to confirm waveform similarity to the ballistocardiogram (BCG) and its reproducibility. We examined the relation between pulse beat arrival time (PBAT) and systolic blood pressure (SBP) and PBAT and pulse arrival time (PAT) after 10 s of VT termination and observed a high negative correlation with SBP and a high positive correlation with PAT in three subjects. cBCG contains components that are strongly related to BP. In future, we will conduct simultaneous measurements with cECG and improve the electrode to simultaneously measure cBCG at two points at constant intervals to avoid shifting of PBAT time axis.

Prostaglandin I2 plays a key role in zymosan-induced mouse pleurisy.

Zymosan, the cell wall of Saccharomyces cerevisiae, induces innate immune responses involving prostanoid production and complement activation. However, the roles of prostanoids in zymosan-induced inflammation and their interaction with the complement system remain to be determined. To clarify these issues, we examined zymosan-induced pleurisy in mice lacking receptors for prostaglandin (PG) E(2) (EP(-/-) mice) or PGI(2) (IP(-/-) mice). Zymosan-induced exudate formation was significantly reduced in IP(-/-) mice compared with wild-type (WT) mice, whereas none of the EP(-/-) mice (EP(1)(-/-), EP(2)(-/-), EP(3)(-/-), and EP(1)(-/-)(4) mice) showed any significant difference from WT mice. Furthermore, indomethacin, an inhibitor of prostanoid biosynthesis, suppressed exudate formation in WT mice to almost the same level as that of IP(-/-) mice. Accordingly, significant production of PGI(2) in the pleural cavity, suggested to be cyclooxygenase-2-dependent, was observed after zymosan injection. Complement activation in the pleural cavity after zymosan injection was confirmed, and preinjection of cobra venom factor (CVF), to deplete blood complement C3, was significantly suppressed after zymosan-induced exudate formation in WT mice. Simultaneous treatment with indomethacin and CVF further suppressed exudate formation in WT mice compared with each treatment alone. Because, some degree of exudate formation was still observed, other factor(s) seem to be involved. However, platelet-activating factor, a promising candidate as one such factor, was not involved in zymosan-induced exudate formation. These results clearly indicate that the PGI(2)-IP system together with the complement system plays a key role in exudate formation in zymosan-induced pleurisy.

Design and Validation of Front-End Voltage Follower for Capacitive Electrocardiogram Measurement Using Bootstrapping Technique.

We addressed design of bootstrapped voltage follower (BVF) in analytical approach from a perspective of capacitive electrocardiogram (cECG) measurement. Theoretical formulas of transfer function, resonant frequency and damping ratio for BVF were derived and experimentally validated. The transfer function and resonant frequency were beneficial for predicting cutoff frequency and frequency-gain characteristics of attenuation band in the low-frequency region. The damping ratio was beneficial for foreseeing occurrences of resonance and distortion in cECG recording. Next challenge is to derive an index inferring settling time after contamination of movement artifact, and to evaluate it experimentally.

Capacitive sensing of electrocardiographic potential through cloth from the dorsal surface of the body in a supine position: a preliminary study.

A method for obtaining electrocardiographic potential through thin cloth inserted between the measuring electrodes and the skin of a subject's dorsal surface when lying supine has been proposed. The method is based on capacitive coupling involving the electrode, the cloth, and the skin. Examination of a pilot device which employed the method revealed the following: (1) In spite of the gain attenuation in the high frequency region, the proposed method was considered useful for monitoring electrogardiogram (ECG) for nondiagnostic purpose. (2) The method was able to yield a stable ECG from a subject at rest for at least 7 h, and there was no significant adverse effect of long-term measurement on the quality of the signal obtained. (3) Electrode area was the factor that had most influence on the signal, compared with other factors such as cloth thickness and coupling pressure, but could be reduced to 10 cm2 for heart rate detection. (4) Input capacitance of the device was assumed to be the dominant factor for the gain attenuation in the high frequency region, and should be reduced with a view to diagnostic use. Although there is still room for improvement in terms of practical use, the proposed method appears promising for application to bedding as a noninvasive and awareness-free method for ECG monitoring.