An analog-AI chip for energy-efficient speech recognition and transcription.

Models of artificial intelligence (AI) that have billions of parameters can achieve high accuracy across a range of tasks1,2, but they exacerbate the poor energy efficiency of conventional general-purpose processors, such as graphics processing units or central processing units. Analog in-memory computing (analog-AI)3-7 can provide better energy efficiency by performing matrix-vector multiplications in parallel on 'memory tiles'. However, analog-AI has yet to demonstrate software-equivalent (SWeq) accuracy on models that require many such tiles and efficient communication of neural-network activations between the tiles. Here we present an analog-AI chip that combines 35 million phase-change memory devices across 34 tiles, massively parallel inter-tile communication and analog, low-power peripheral circuitry that can achieve up to 12.4 tera-operations per second per watt (TOPS/W) chip-sustained performance. We demonstrate fully end-to-end SWeq accuracy for a small keyword-spotting network and near-SWeq accuracy on the much larger MLPerf8 recurrent neural-network transducer (RNNT), with more than 45 million weights mapped onto more than 140 million phase-change memory devices across five chips.

Variables influencing patient satisfaction for hypnotics: difference between zolpidem and brotizolam.

WHAT IS KNOWN AND OBJECTIVE: The pharmacokinetics of zolpidem and brotizolam is affected by gender and age, that is, increased clearance in males taking zolpidem and younger subjects taking brotizolam. The purpose of this study was to determine the variables including gender and age influencing patient satisfaction for hypnotics, zolpidem and brotizolam. METHODS: The study included 329 patients who were treated with zolpidem (n = 172) and brotizolam (n = 157) for insomnia. Patients were interviewed to evaluate individual satisfaction and drug efficacy. The factors associated with dissatisfaction of zolpidem and brotizolam were identified using multiple logistic analysis. RESULTS AND DISCUSSION: Of the participating patients, 40 (23%) and 41 (26%) complained of dissatisfaction with zolpidem and brotizolam, respectively. An insufficient amount of sleep (<6 h) and the number of awakenings were common factors cited for dissatisfaction for both drugs. Males were found to report a higher rate of dissatisfaction for zolpidem, whereas patients younger than 65 years and those receiving corticosteroid therapy reported a higher rate of dissatisfaction with brotizolam. WHAT IS NEW AND CONCLUSION: These results suggested that patient satisfaction was different between zolpidem and brotizolam in terms of gender for zolpidem and age and corticosteroid co-administration for brotizolam, which could be used to help choose a better drug among the two in patients with insomnia.

Long-term observation of renal function on combination therapy with prostaglandin and angiotensin-converting enzyme inhibitor for chronic kidney disease.

AIMS: Recently, we reported the effectiveness of PAC therapy, a combination therapy with prostaglandin (PG) and angiotensin-converting enzyme inhibitor (ACE-I), as a new tool for the prevention of chronic kidney disease. In the current study, we continually treated these patients with or without PG and analyzed the survival rate of renal function by Kaplan-Meier method and Cox regression analysis. MATERIAL AND METHODS: 52 patients (serum creatinine 2.9 A+/- 1.9 mg/dl) were followed-up for 48 months. 26 patients continued to receive ACE-I monotherapy and the remaining 26 patients were treated by PAC therapy. Primary end-point was defined as a decrease in 1/Cr by 0.2 (dl/mg), initiation of renal replacement therapy or death. RESULTS: At the end of the study, PAC therapy significantly reduced the risk for the decline in renal function compared to ACE-I monotherapy by 54%. Survival time was longer in PAC group (21.7 A+/- 2.2 and 35.1 A+/- 3.9 months, in ACE-I monotherapy and PAC therapy, p < 0.05). Cox regression analysis indicated that age, sex and blood pressure except urinary protein excretion did not relate to the risk reduction by PAC therapy. CONCLUSION: PAC therapy was proved to reduce the progression of end-stage renal failure.

Assessment of hypnotic effects and patient satisfaction in empirical use of sleep medicines.

OBJECTIVE: We assessed the hypnotic effects of and patient satisfaction with three types of hypnotics prescribed empirically: ultra-short-acting (US-a), short-acting (S-a), and intermediate- and long-acting (IL-a) agents. METHODS: We studied 310 insomniac patients (age 60.5 +/- 15.0 years) treated with US-a (n = 124), S-a (n = 149) or IL-a (n = 37) agents. Patients were interviewed to evaluate individual satisfaction and drug efficacy. Efficacy, as assessed by total sleep time (TST) and sleep latency time (SLT), was compared between satisfied and dissatisfied patient groups. Nocturnal awaking curve for each hypnotic was used for comparing the effects between satisfied and dissatisfied patient groups in each type of hypnotics. RESULTS: Thirty-two patients (25.8%) were dissatisfied with US-a, 35 (23.5%) with S-a and 11 (29.7%) with IL-a. TST differed significantly between satisfied and dissatisfied groups: 424 +/- 88 vs. 345 +/- 101 min for US-a (P < 0.001), 440 +/- 84 vs. 359 +/- 111 min for S-a (P < 0.001) and 453 +/- 96 vs. 345 +/- 125 min for IL-a (P < 0.01), respectively. With IL-a agents, the SLT of dissatisfied patients was longer than in satisfied ones (81 +/- 52 vs. 33 +/- 22 min, P < 0.05). Twenty (62.5%) dissatisfied patients taking US-a agents awoke before 05:00 hours - a rate significantly higher than satisfied patients (n = 23, 25.0%, P < 0.001). These characteristics of dissatisfied patients were reflected by the patterns of nocturnal awaking curves, although the patterns for satisfied patients were similar among the three types of hypnotics. CONCLUSION: Between 24% and 30% of patients were dissatisfied with their hypnotics. Shorter TST was common in dissatisfied patients receiving any agent, for reasons differing among hypnotics (longer SLT with IL-a agents and early awakening with US-a). Drug efficacy and patient satisfaction in empirical use of hypnotics can be assessed by nocturnal awaking curves for each hypnotic.

Blood ribavirin concentration in high-dose ribavirin for adenovirus-induced haemorrhagic cystitis - a case report.

Blood ribavirin concentration was monitored after the administration of high-dose oral ribavirin in a case of adenovirus-induced haemorrhagic cystitis post-stem-cell transplantation. Combination use of intravenous gamma immunoglobulin (15 g/3 days) and high-dose ribavirin (RBV; 9000 mg/4 days) provided plasma ribavirin concentration of 24.3 microM and achieved virus eradication. High level of erythrocyte ribavirin (1085 microM; mostly as phosphorylated metabolites) with long half-life (15 days) caused severe anaemia, which required several blood transfusions for 2 weeks after the cessation of the ribavirin treatment. It was suggested that blood transfusion and intensive haemoglobin level monitoring is necessary for at least 4 weeks after the RBV, because of the high accumulation of phosphorylated ribavirin in erythrocytes even after stopping ribavirin administration.

Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats.

Reperfusion after ischemia induces cytokines, chemoattractant chemokines, adhesion molecules, and nitric oxide (NO). The resultant neutrophil adherence and NO potentiates renal injury. alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent anti-inflammatory agent that inhibits neutrophil migration and production of neutrophil chemokines and NO. Since neutrophils and NO promote renal ischemic injury, we sought to determine if alpha-MSH inhibits renal injury in a model of bilateral renal ischemia. alpha-MSH significantly reduced ischemia-induced renal damage, measured by changes in renal histology and plasma blood urea nitrogen and creatinine in mice. alpha-MSH significantly decreased tubule necrosis, neutrophil plugging, and capillary congestion. Delay of alpha-MSH treatment for 6 h after ischemia also significantly inhibited renal damage. alpha-MSH also significantly inhibited ischemic damage in rats. To begin to determine the mechanism of action of alpha-MSH, we measured its effects on mediators of neutrophil trafficking and induction of the inducible isoform of NO synthase-II. alpha-MSH inhibited ischemia-induced increases in mRNA for the murine neutrophil chemokine KC/IL-8. alpha-MSH also inhibited induction of mRNA for the adhesion molecule ICAM-1, which is known to be critical in renal ischemic injury. alpha-MSH inhibited nitration of kidney proteins and induction of NO synthase-II. We conclude: (a) alpha-MSH protects against renal ischemia/reperfusion injury; and (b) it may act, in part, by inhibiting the maladaptive activation of genes that cause neutrophil activation and adhesion, and induction of NO synthase.

Low-responders to angiotensin II receptor blockers and genetic polymorphism in angiotensin-converting enzyme.

AIMS: The existence of low-responders to angiotensin II receptor blockers (ARBs) in terms of the preservation of renal function is reported here. We investigated the relationship between the responsiveness to ARBs and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. METHODS: The effects of ARBs on proteinuria and the progression of chronic renal failure were examined in 113 patients with chronic kidney disease for 34 months before and 27 months after the addition of ARBs. RESULTS: Although a decrease in blood pressure was seen in the II, DI and DD patient subgroups of the ACE gene, the decrease in proteinuria and the amelioration of loss of renal function were observed in the II and DI but not in the DD patients. Kaplan-Meier analysis was employed with a decrease of the reciprocal of serum creatinine of more than 0.2, the induction of renal replacement therapy or death as endpoints. The analysis comparing the periods before and after the addition of ARBs revealed the extension of time to an end-point by the addition of ARBs in all groups together (II + DI + DD), in Group II, and Group DI but not in the DD patient Group. CONCLUSIONS: These data suggest that DD patients with ACE gene demonstrate diminished response to ARBs in terms of renoprotection and that ACE gene polymorphism needs to be taken into account when using ARBs as a means of renoprotective therapy.

Angiotensin-converting enzyme inhibitor withdrawal and ACE gene polymorphism.

AIMS: Withdrawal of angiotensin-converting enzyme (ACE) inhibitors may affect the progression of chronic renal failure and an insertion/deletion (I/D) polymorphism of the ACE gene may influence it. METHODS: We retrospectively collected patients with chronic glomerulonephritis and benign nephrosclerosis who discontinued ACE inhibitor use. The relationship between the decline of renal function after the withdrawal and the influencing factors such as ACE gene polymorphism, blood pressure and proteinuria were evaluated using multiple regression analysis. RESULTS: Forty-two patients (initial serum creatinine 0.5 - 6.5 mg/dl) had been treated and discontinued ACE inhibitor use. Only patients with the II or DI genotypes of the ACE gene developed the deterioration of renal function, starting at 2 months after the withdrawal. Stepwise regression analysis revealed that the level of proteinuria after the withdrawal, presence of the insertion of ACE gene and serum creatinine level at the time of withdrawal mainly influenced the decline of renal function after the withdrawal (adjusted R2 = 0.48). CONCLUSION: Withdrawal of ACE inhibitor causes the deterioration of renal function in patients with the II or DI genotypes, high proteinuria after the withdrawal, and high serum creatinine level at the withdrawal, which probably causes the rebound increase in serum ACE activity.

Effect of plasma alpha1-acid glycoprotein concentration on the accumulation of lidocaine metabolites during continuous epidural anesthesia in infants and children.

OBJECTIVE: Alpha1-acid glycoprotein (AAG) is an acute-phase protein that is responsible for binding basic drugs such as lidocaine (LDC). The effect of AAG on the duration of LDC during continuous epidural anesthesia in infants and young children was investigated. PATIENTS, MATERIALS AND METHODS: Plasma levels of LDC and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were monitored in 20 infants and children, 5 months to 6 years of age, who received continuous epidural infusion of 2.5 mg kg(-1) LDC hourly during abdominal or thoracic surgeries. RESULTS: Plasma LDC concentrations were constant after the first hour of injection. In contrast, the concentrations of MEGX and GX increased continuously during epidural infusion in all patients. The plasma AAG concentration correlated significantly (r = 0.814, p<0.001) with the steady-state LDC level. In addition, significant inverse correlation was observed between the plasma AAG concentration and the accumulation rate of MEGX (r = 0.742, p = 0.002). The plasma AAG concentration and the accumulation rate of GX correlated weakly (r = 0.474, p = 0.035). There was no correlation between the age of the patient and the plasma AAG concentrations (r = 0.295, p = 0.206). CONCLUSION: Our results suggest that the plasma AAG concentration is a valuable index in preventing the toxicity caused by accumulation of MEGX during continuous epidural anesthesia of LDC.

Chromatographic determination of free lidocaine and its active metabolites in plasma from patients under epidural anesthesia.

OBJECTIVE: We developed a simple and selective assay method for simultaneous determination of free lidocaine (LDC) and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX) in plasma, by using high-performance liquid chromatography (HPLC). The method was applied to the plasma concentration monitoring in continuous epidural anesthesia with LDC. MATERIALS AND METHODS: Free fraction was separated from plasma by using an ultrafiltration technique. Free and total LDC, MEGX and GX in plasma were analyzed by HPLC equipped with ordinary octadecylsilyl silica (ODS) column and ultraviolet (UV) detector. PATIENTS: Five male patients with cancer who received epidural injection of 1.5% LDC for 5 hours in elective thoracic surgery, were enrolled to determine the plasma levels of total and free LDC, MEGX and GX. RESULTS AND DISCUSSION: The calibration curve for free LDC, MEGX and GX were linear at the concentration of 25 to 1,000 ng ml(-1) (r = 0.9998 - 0.9999). The recoveries for LDC, MEGX and GX from plasma water were ranged 73.2-89.1%. The coefficient variations for intra- and inter-day assay for LDC, MEGX and GX were less than 4.1%. The detection limit ofeach drug was 20 ng ml(-1). Plasma-free MEGX after 180 min epidural injection was higher than free LDC, even though the total concentration of MEGX was 4 times lower than that of LDC. The percentages of free fraction for LDC, MEGX and GX were 11.7, 48.5 and 78.3% after 5-hour epidural administration of LDC. Since the free fraction of MEGX and GX increases and exceeds the concentration of free LDC during continuous epidural anesthesia, accumulation of these toxic metabolites should be carefully monitored as well as LDC. CONCLUSION: The present method is a reliable technique and can be applied to monitoring free LDC, MEGX and GX, which provide us beneficial information as to the LDC metabolism and toxicity.

Plasma lidocaine, monoethylglycinexylidide, and glycinexylidide concentrations after epidural administration in geriatric patients.

BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate the effect of age on the pharmacokinetics of lidocaine after epidural administration. METHODS: Two percent lidocaine with epinephrine (5 microg/mL) was administered in two different age groups: an adult group (age 42 +/- 6 years, n = 10) and an elderly group (age 77 +/- 4 years, n = 10). Concentrations of lidocaine and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were measured in plasma samples obtained after 15, 30, 45, 60, 90, 120, 150, and 180 minutes of administration using high-performance liquid chromatography with ultraviolet detection. RESULTS: No significant differences in plasma concentrations of lidocaine and its metabolites were observed between the two groups during the 3 hours of study. However, the elderly group showed significantly longer mean residence times (MRTs) and lower plasma clearance of lidocaine during the period compared with the adult group (P < .05). Plasma concentration ratios of MEGX/lidocaine were significantly lower in the elderly group after 2 hours of lidocaine administration (P < .05). CONCLUSIONS: The increase in plasma lidocaine concentration after epidural anesthesia in elderly patients was not as high as anticipated. However, the elderly patients showed longer MRTs, lower clearance, and lower ratios of MEGX/lidocaine than did the adult (middle-age) patients.

Plasma concentrations of lidocaine and its principal metabolites during continuous epidural infusion of lidocaine with or without epinephrine.

BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate the effect of epinephrine on the absorption of lidocaine and the accumulation of active metabolites of lidocaine during continuous epidural anesthesia. METHODS: Lidocaine was administered as an initial bolus of 5 mg/kg of 2% lidocaine solution followed by continuous infusion at 2.5 mg/kg/h. Patients in group I (n = 10) received lidocaine alone and patients in group II (n = 10) received lidocaine + epinephrine (5 pg/mL). Concentrations of lidocaine and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were measured in plasma samples obtained after 15 minutes, 30 minutes, and 1, 2, and 3 hours of infusion using high-performance liquid chromatography with ultraviolet detection. RESULTS: Plasma lidocaine concentrations were higher in group I for the first 30 minutes; however, after 1 hour the levels were the same. Plasma MEGX and GX increased continuously in both groups. MEGX levels the were significantly higher in group I, but there was no significant difference in the sum of lidocaine + MEGX after 2 hours. There was no significant difference in GX levels between the two groups. CONCLUSIONS: With respect to continuous epidural administration, addition of epinephrine to lidocaine solutions is ineffective after 2 hours for reducing the potential for systemic toxicity, because the sum of the plasma concentrations of lidocaine and its principal active metabolite, MEGX, are unaffected.

Protein binding of glufosinate and factors affecting it revealed by an equilibrium dialysis technique.

We investigated the protein binding of glufosinate ammonium (GLF) and several factors affecting this binding using human serum albumin (HSA) and human volunteer serum under various conditions. The mean ratios of the free GLF (RFr-GLF) to 4% HSA were examined in the sera of patients described elsewhere at GLF levels from 1 microg/mL to 500 microg/mL; the range was found to be only from 0.80 to 0.88. Neither the incubation temperature nor buffers containing different chloride ion concentrations had any effect on the RFr-GLF to HSA. Moreover, the addition of heparin, glycoprotein-alpha1-acid (AAG), and sodium azide had no effect on the RFr-GLF. However, pH of the isotonic phosphate buffer and the addition of palmitic or oleic acid were seen to have an effect. In this study, the mean RFr-GLF to healthy human serum was 0.99. This high value was evidenced that GLF was rapidly excreted through the renal route.

A toxicokinetic analysis in a patient with acute glufosinate poisoning.

Incidents of poisoning in humans caused by the ingestion of the glufosinate ammonium containing herbicides are gradually increasing in Japan. This poisoning is characterized by various neurological symptoms such as disturbances of consciousness, convulsions and apnea which appear after an asymptomatic interval of several hours. We studied the toxicokinetics of glufosinate in a patient with this poisoning successfully treated without extracorporeal hemopurification. A 65-year-old male ingested BASTA, which contains 20% w/v of glufosinate ammonium, about 300 ml, more than the estimated human toxic dose. Four and a half hours after ingestion, he showed speech ataxia and systemic tremor. He was prophylactically intubated before the occurrence of serious respiratory failure. After 5 days of artificial ventilation he was extubated and discharged without any sequelae. We studied the serial change of serum glufosinate concentration every 3-6 h and assessed the urinary excretion of glufosinate every 24 h. The absorbed amount of glufosinate was estimated from the cumulative excreted in urine. Toxicokinetic analysis was performed using the two-compartment model. The changes in serum glufosinate concentration exhibited T1/2alpha of 1.84 and T1/2beta of 9.59 h. The apparent distribution volume at beta-phase and the total body clearance were 1.44 l/kg and 86.6 ml/min, respectively. Renal clearance was estimated to be 77.9 ml/min. The indication for extracorporeal hemopurification for this poisoning has been discussed.

[Development and evaluation of the comment aid system for therapeutic drug monitoring. I. Application to valproate].

A comment aid system for therapeutic drug monitoring (TDM), which produces the primary comment on the dosage regimen of valproate, was developed. This system produces consulting comments with a fuzzy theory, by using the dosage regimen of valproate, pharmacokinetic parameters estimated by the Bayesian method, and therapeutic effect and toxicity of anticonvulsants evaluated by the physician. For nearly 90% in 42 cases, comments of the system were agreeable comparing with the notes of TDM technologists. There are a few disagreements between this system and experts, mainly because the system does not use enough information about combination therapy with other anticonvulsants. Developed comment aid system shows some clinical and educational utility, and suggests significance and possibility of more useful and al around TDM expert system. Then this system might be available as a prototype of the TDM expert system.

[Preparation and clinical evaluation of orally-disintegrating clonidine hydrochloride tablets for preanesthetic medication].

Orally-disintegrating tablets of clonidine hydrochloride, an alpha 2-adrenergic agonist, were prepared by the method of drying an aqueous suspension. The suspension was prepared using powdered lactose, and the composition ratio was 2:1 (powdered lactose: 0.048% clonidine hydrochloride solution). The suspension was dried under 4 +/- 1 degrees C (72 +/- 15% R.H.). We obtained tablets containing clonidine hydrochloride (40 micrograms/tablet). Physical properties of the tablets were as follows: hardness was 4.0 kgf, and disintegration time was 41.7 s (in vitro). In the clinical use, 8 patients, aged 1-2 year and weighing 9-11 kg, received approximately 4 micrograms/kg body weight as clonidine hydrochloride. The tablet was administered 90 min before entering the operating room. All patients were willing to accept the tablet. The quality of separation from parents, sedation and a mask acceptance were excellent on all patients. These results suggest that the orally-disintegrating tablet of clonidine hydrochloride was useful in a clinical situation for the preanesthetic medication of pediatric patients aged 1-2 year.

[Consultation and survey for drug interaction in outpatients taking the medicines potentially interact with St. John's Wort].

Ministry Health Welfare of Japan announced the caution for drug interaction of St. John's Wort (SJW), a herbal supplement occasionally used for depression, on May, 2000. Immediately after the announcement, we conducted drug consultation for outpatients prescribed the medicines potentially interacting with SJW. We provided information concerning possible drug interaction with SJW for 741 outpatients (except for pediatrics) during the period of May 22-June 16, 2000. The potential drugs prescribed frequently were warfarin (28.0%), theophylline (19.7%), digitalis (18.4%), carbamazepine (7.2%), disopyramide (6.9%) and cyclosporin (6.3%). Of the patients, 401 subjects were surveyed by collecting the questionnaires to clarify the background of SJW drug interaction. Twenty-two subjects (5.5%) have known commercially available SJW products, 5 subjects (1.2%) have ever taken SJW products before and 2 subjects (0.5%) have taken SJW products concomitant with prescribed medicines. Gender difference was observed in paying attention to SJW products; female subjects (8.6%) tended to have more interest in SJW products than male subjects (2.8%). Two subjects taking SJW have realized for the first time that the supplements they took were SJW products when their package photographs were shown at the consultation. Showing the package photographs might be helpful for making the patients easy to identify the SJW products, because most patients do not pay attention to whether the supplements contain SJW or not. It is recommended that drug consultation should be provided to avoid serious drug interaction with SJW while the outpatients are taking potential medicines prescribed.

[A new departure of an incorporated round visits; anesthesiologists and pharmacists ].

We commenced a new trial of an incorporated round visit. Members of round visit are 4 anesthesiologists and 2 pharmaceutists. This new trial gives us the following advantages; 1. We can get the newest drug informations at bed side during the round visit. 2. We can select a more reasonable therapy for patients through discussions. 3. Cooperative development of clinical studies concerning a new model or style of drugs may be possible. This new style of round visit is also of benefit for patients because it leads to administration of more pertinent drugs. We recommend to have a chance of cooperation between anesthesiologists and pharmaceutists in other hospitals.

[Study on human diseased thyroid cells in collagen gel culture--morphology and their malignancy of cultured colonies].

Thyroid cells from 14 normal subjects, two patients with Grave's disease, four patients with follicular adenoma and eight patients with papillary carcinoma were cultured in collagen gel. The colonies of these cells were stereoscopically observed and their morphological characteristics were studied with regard to relation with pathological findings of mother tumor, extra-capsular invasion and metastatic potential. For normal thyroid, Grave's disease and follicular adenoma (except for one case), their own characteristic branching type colonies were found. For papillary carcinoma, both branching type and spheroid type of colonies were observed. The ratio of branching type/spheroid type varied individually in the patients with papillary carcinoma. However, the spheroid type was found to trend to be predominant in patients with extra-capsular invasion and/or lymph node metastasis. This means that the observation of spheroid type colonies in collagen gel is suggestive of risk of extra-capsular invasion or lymph node metastasis. From the obtained results, it seemed possible to diagnose poorly-differentiated cells in vitro by morphologically observing colonies of human thyroid papillary carcinoma cells developing in collagen gel.