Detection of intraductal carcinoma in prostate cancer patients with small tumor volume.

OBJECTIVES: The purpose of this study was to investigate intraductal carcinoma of the prostate (intraductal carcinoma) and significant cancer (SC) in patients with small tumor volume (<0.5 cm3 ) in prostatectomy specimens. METHODS: Data from 639 patients undergoing radical prostatectomy between April 2006 and December 2017 at Chiba University Hospital and 2 affiliated institutions were retrospectively reviewed. Tumor volume in prostatectomy specimens was measured, and with a tumor volume of less than 0.5 cm3 , the presence of intraductal carcinoma and SC was examined. SC was defined as one that did not meet the definition of pathological insignificant cancer (organ-confined cancer, Grade Group 1, tumor volume < 0.5 cm3 ). The number of patients who met four active surveillance (AS) protocols was also examined. RESULTS: A total of 83 patients with tumor volume < 0.5 cm3 were identified in this study population (SC: 43 patients [52%], intraductal carcinoma: 5 patients [6%]). The median follow-up was 34.6 months (range: 18-57 months). Four (5%) developed biochemical recurrence. The number of positive biopsy cores ≥ 2 was an independent predictor of SC in patients with tumor volume < 0.5 cm3 (hazard ratio: 4.39; 95% confidence interval: 1.67-11.56; p = 0.003). In tumor volume < 0.5 cm3 , tumor volume was significantly correlated with the International Society of Urological Pathology Grade Group (1 vs. 4-5, p = 0.002) and the presence of intraductal carcinoma (p = 0.004). In intraductal carcinoma-positive cases, four of five patients (80%) had the predictor of SC, which was two or more positive biopsy cores. Of the four AS protocols, the criteria for Prostate Cancer Research International: Active Surveillance were met most frequently in 46 cases (55%) of tumor volume less than 0.5 cm3 if targeted biopsy by magnetic resonance imaging was available. CONCLUSION: The results of the present study suggest that intraductal carcinoma was present even in cases with small tumor volumes. Grade Group and intraductal carcinoma showed a positive correlation with tumor volume.

Chemotherapy-induced leukopenic septic shock treated with veno-arterial extracorporeal membrane oxygenation: A case report.

We present a case of chemotherapy-induced leukopenic septic shock treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Although the indication for VA-ECMO for septic shock in immunosuppressed states remains controversial, her relatively young age and a slightly increasing leukocyte count led to VA-ECMO induction and resulted in recovery.

Validation of the patient State Index for monitoring sedation state in critically ill patients: a prospective observational study.

PURPOSE: The Patient State Index (PSI) is a newly introduced electroencephalogram-based tool for objective and continuous monitoring of sedation levels of patients under general anesthesia. This study investigated the potential correlation between the PSI and the Richmond Agitation‒Sedation Scale (RASS) score in intensive care unit (ICU) patients and established the utility of the PSI in assessing sedation levels. METHODS: In this prospective observational study, PSI values were continuously monitored via SedLine® (Masimo, Irvine, CA, USA); the RASS score was recorded every 2 h for patients on mechanical ventilation. Physicians and nurses were blinded to the PSI values. Overall, 382 PSI and RASS score sets were recorded for 50 patients. RESULTS: The PSI score correlated positively with RASS scores, and Spearman's rank correlation coefficient between the PSI and RASS was 0.79 (95% confidence interval [CI]: 0.75‒0.83). The PSI showed statistically significant difference among the RASS scores (Kruskal‒Wallis chi-square test: 242, df = 6, P < 2.2-e16). The PSI threshold for distinguishing light (RASS score ≥ - 2) sedation from deep sedation (RASS score ≤ - 3) was 54 (95% CI: 50-65; area under the curve, 0.92 [95% CI: 0.89‒0.95]; sensitivity, 0.91 [95% CI: 0.86‒0.95]; specificity, 0.81 [95% CI: 0.77-0.86]). CONCLUSIONS: The PSI correlated positively with RASS scores, which represented a widely used tool for assessing sedation levels, and the values were significantly different among RASS scores. Additionally, the PSI had a high sensitivity and specificity for distinguishing light from deep sedation. The PSI could be useful for assessing sedation levels in ICU patients. University Hospital Medical Information Network (UMIN000035199, December 10, 2018).

An Automated Algorithm for Determining Sleep Using Single-Channel Electroencephalography to Detect Delirium: A Prospective Observational Study in Intensive Care Units.

The relationship between polysomnography-based objective sleep and delirium in the intensive care unit (ICU) is inconsistent across studies, suggesting limitations in manually determining the sleep stage of critically ill patients. We objectively measured 24-h sleep using a single-channel electroencephalogram (SleepScope [SS]) and an under-mattress sleep monitor (Nemuri SCAN [NSCAN]), both of which have independent algorithms that automatically determine sleep and wakefulness. Eighteen patients (median age, 68 years) admitted to the ICU after valvular surgery or coronary artery bypass grafting were included, and their sleep time was measured one day after extubation. The median total sleep times (TSTs) measured by SS (TST-SS) and NSCAN were 548 (48−1050) and 1024 (462−1257) min, respectively. Two patients with delirium during the 24-h sleep measurement had very short TST-SS of 48 and 125 min, and the percentage of daytime sleep accounted for >80% in both SS and NSCAN. This preliminary case series showed marked sleep deprivation and increased rates of daytime sleeping in ICU patients with delirium. Although data accuracy from under-mattress sleep monitors is contentious, automated algorithmic sleep/wakefulness determination using a single-channel electroencephalogram may be useful in detecting delirium in ICU patients and could even be superior to polysomnography.

The Reduction in Medical Errors on Implementing an Intensive Care Information System in a Setting Where a Hospital Electronic Medical Record System is Already in Use: Retrospective Analysis.

BACKGROUND: Although the various advantages of clinical information systems in intensive care units (ICUs), such as intensive care information systems (ICISs), have been reported, their role in preventing medical errors remains unclear. OBJECTIVE: This study aimed to investigate the changes in the incidence and type of errors in the ICU before and after ICIS implementation in a setting where a hospital electronic medical record system is already in use. METHODS: An ICIS was introduced to the general ICU of a university hospital. After a step-by-step implementation lasting 3 months, the ICIS was used for all patients starting from April 2019. We performed a retrospective analysis of the errors in the ICU during the 6-month period before and after ICIS implementation by using data from an incident reporting system, and the number, incidence rate, type, and patient outcome level of errors were determined. RESULTS: From April 2018 to September 2018, 755 patients were admitted to the ICU, and 719 patients were admitted from April 2019 to September 2019. The number of errors was 153 in the 2018 study period and 71 in the 2019 study period. The error incidence rates in 2018 and 2019 were 54.1 (95% CI 45.9-63.4) and 27.3 (95% CI 21.3-34.4) events per 1000 patient-days, respectively (P<.001). During both periods, there were no significant changes in the composition of the types of errors (P=.16), and the most common type of error was medication error. CONCLUSIONS: ICIS implementation was temporally associated with a 50% reduction in the number and incidence rate of errors in the ICU. Although the most common type of error was medication error in both study periods, ICIS implementation significantly reduced the number and incidence rate of medication errors. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000041471; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047345.

Universal association between depressive symptoms and social-network structures in the workplace.

An unhealthy communication structure at a workplace can adversely affect the mental health of employees. However, little is known about the relationship between communication structures in the workplace and the mental health of employees. Here, we evaluated the face-to-face interaction network among employees (N = 449) in a variety of real-world working environments by using wearable devices and investigated the relationship between social network characteristics and depressive symptoms. We found that the cohesive interaction structure surrounding each individual was negatively correlated with depressive symptoms: a universal relationship regardless of occupation type. This correlation was evident at the group scale and was strongly related to active interactions with abundant body movement. Our findings provide a quantitative and collective perspective on taking a systematic approach to workplace depression, and they suggest that the mental health of employees needs to be addressed systematically, not only individually.

Catheter-related thrombosis after cardiac surgery in patients with both central venous and pulmonary artery catheters inserted into the right internal jugular vein: a single-center, prospective, observational study.

Central venous catheters (CVCs) and pulmonary artery catheters (PACs) are widely used in intensive care and perioperative management. The detection and prevention of catheter-related thrombosis (CRT) are important because CRT is a complication of catheter use and can cause pulmonary embolism and bloodstream infection. Currently, there is no evidence for CRT in patients using both CVC and PAC. We conducted a single-center, prospective, observational study to identify the incidence, timing, and risk factors for CRT in patients undergoing cardiovascular surgery and using a combination of CVC and PAC through the right internal jugular vein (RIJV). Out of 50 patients, CRT was observed using ultrasonography in 39 patients (78%), and the median time of CRT formation was 1 day (interquartile range: 1-1.5) after catheter insertion. The mean duration of PAC placement was 3 days (interquartile range: 2-5), and the maximum diameter of CRT was 12 mm (interquartile range: 10-15). In short-axis images, CRT occupied more than half of the cross-sectional area of the RIJV in five patients (10%), and CRT completely occluded the RIJV in one patient (2%). Platelet count, duration of PAC placement, and intraoperative bleeding amount were found to be high-risk indicators of CRT. In conclusion, patients who underwent cardiovascular surgery and using both CVC and PAC had a high incidence of CRT. Avoiding unnecessary PAC placement and early removal of catheters in patients at high risk of developing CRT may prevent the development of CRT.

In Vivo Pharmacodynamics of ß-Lactams/Nacubactam against Carbapenem-Resistant and/or Carbapenemase-Producing Enterobacter cloacae and Klebsiella pneumoniae in Murine Pneumonia Model.

Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) have become global threats. CRE- and CPE- derived infections have been associated with high mortality due to limited treatment options. Nacubactam is a ß-lactamase inhibitor and belongs to the new class of diazabicyclooctane. The agent has an in vitro antimicrobial activity against several classes of ß-lactamase-producing Enterobacterales. This study evaluated antimicrobial activity of combination therapies including ß-lactams (aztreonam, cefepime, and meropenem) and nacubactam against four Enterobacter cloacae and six Klebsiella pneumoniae isolates with murine pneumonia model. Based on changes in bacterial quantity, antimicrobial activities of some regimens were assessed. Combination therapies including ß-lactams (aztreonam, cefepime, and meropenem) with nacubactam showed enhanced antimicrobial activity against CRE E. cloacae (-3.70 to -2.08 Δlog10 CFU/lungs) and K. pneumoniae (-4.24 to 1.47 Δlog10 CFU/lungs) with IMP-1, IMP-6, or KPC genes, compared with aztreonam, cefepime, meropenem, and nacubactam monotherapies. Most combination therapies showed bacteriostatic (-3.0 to 0 Δlog10 CFU/lungs) to bactericidal (<-3.0 Δlog10 CFU/lungs) activities against CRE isolates. This study revealed that combination regimens with ß-lactams (aztreonam, cefepime, and meropenem) and nacubactam are preferable candidates to treat pneumonia due to CRE and CPE.

Estimating Group Stress Level by Measuring Body Motion.

Understanding employee stress has become a key issue for top management for corporate growth and risk reduction. So far, annual employee satisfaction surveys (ESs) have been conducted to assess the soundness of an organization. However, since it is difficult to collect questionnaires quantitatively and continuously, there is a need for a practical method that can be used to frequently measure group stress levels with a small burden on employees. We propose such a method and evaluated four combinations of approaches, using activity/rest duration distributions from body motion data and generating estimation models on an individual/group basis. The optimal result was obtained when modeling was made on a group basis by using the activity duration distribution (r = 0.928, p < 0.001, estimation error: 1.36%), making it possible to assess the degree of the stress of employees quantitatively and easily, and this showed the possibility of this method being useful as a management guide for companies.

Prognostic Value of High-Sensitivity Modified Glasgow Prognostic Score in Castration-Resistant Prostate Cancer Patients Who Received Docetaxel.

The Glasgow prognostic score, a marker of systemic inflammation, is associated with clinical outcomes in different cancers including prostate cancer. However, there is no evidence for the relationship between the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) in prostate cancer and its prognosis. This study aimed to investigate the prognostic significance of Hs-mGPS in castration-resistant prostate cancer (CRPC) treated with docetaxel. We retrospectively analyzed clinical datasets from 131 CRPC patients who received docetaxel treatment at Chiba University Hospital and a related hospital. Clinical factors including Hs-mGPS before docetaxel treatment were evaluated according to overall survival. The numbers of patients with Hs-mGPS of 0, 1, and 2 were 88, 30, and 13, respectively. The median prostate-specific antigen (PSA) level was 28.9 ng/mL. The median testosterone level was 13.0 ng/dL. The percentages of bone and visceral metastases were 80.8% and 10.2%, respectively. For overall survival, Hs-mGPS ≥ 1 (hazard ratio of 2.41; p = 0.0048), testosterone ≥ 13.0 ng/dL (hazard ratio of 2.23; p = 0.0117), and PSA ≥ 28.9 ng/mL (hazard ratio of 2.36; p = 0.0097) were significant poor prognostic factors in the multivariate analysis. The results of the two-group analysis showed that a higher Hs-mGPS was associated with high PSA, alkaline phosphatase, and testosterone levels. The median testosterone levels for Hs-mGPS of 0, 1, and 2 were 9.0, 16.5, and 23.0, respectively. Based on the multivariate analysis, we created a combined score with three prognostic factors: Hs-mGPS, testosterone, and PSA. The low-risk group (score of 0-1) showed a significantly longer overall survival compared to the intermediate-risk (score of 2-3) and high-risk (score of 4) groups (p < 0.0001). Our results demonstrated that an elevated Hs-mGPS was an independent prognostic factor in CRPC patients treated with docetaxel therapy. Risk classification based on Hs-mGPS, testosterone, and PSA may be useful in predicting the prognosis of CRPC patients.

Pharmacodynamic evaluation of meropenem, cefepime, or aztreonam combined with a novel ß-lactamase inhibitor, nacubactam, against carbapenem-resistant and/or carbapenemase-producing Klebsiella pneumoniae and Escherichia coli using a murine thigh-infection model.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) are difficult to treat and are a serious public health threat. Nacubactam (NAC) is a novel non-ß-lactam diazabicyclooctane ß-lactamase inhibitor with in vitro activity against some Enterobacterales expressing classes of ß-lactamases. METHODS: The antimicrobial efficacy of meropenem (MEM), cefepime (FEP), and aztreonam (ATM), each in combination with NAC, were assessed in vitro and in vivo against Klebsiella pneumoniae and Escherichia coli. Ten isolates, including CRE and/or CPE with ß-lactamase genes, were used in this study. The relationship between phenotype and in vivo efficacy was assessed in a murine neutropenic thigh-infection model. Efficacy was determined by the change in bacterial quantity. RESULTS: The results of the in vitro study showed the minimum inhibitory concentrations of the combination of NAC with either MEM, FEP, or ATM in a 1:1 ratio were 2 to >128-fold lower than those of MEM, FEP, or ATM alone against CRE+ isolates. In addition, combinations of ß-lactams and NAC administered in the murine thigh-infection model showed greater efficacy against CRE+/CPE+, CRE+/CPE-, and CRE-/CPE+ isolates harboring various ß-lactamase genes (IMP-1, IMP-6, KPC, DHA-1, or OXA-48) compared with MEM, FEP, ATM, and NAC alone. CONCLUSION: MEM, FEP, or ATM in combination with NAC showed potent in vivo antimicrobial activity in a murine thigh-infection model caused by K. pneumoniae and E. coli, including CRE and/or CPE isolates. These findings indicate that these combinations of ß-lactams and NAC are potential candidates for the treatment of CRE and/or CPE infections.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution.

ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus Percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 µg/ml), P. aeruginosa (4 µg/ml), and S. aureus (0.5 µg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2 ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

Higher serum testosterone levels predict poor prognosis in castration-resistant prostate cancer patients treated with docetaxel.

BACKGROUND: The role of testosterone as a prognostic factor for castration-resistant prostate cancer treated with docetaxel in Japan was investigated. METHODS: A total of 164 patients with castration-resistant prostate cancer who received docetaxel treatment at Chiba University Hospital and an affiliated hospital were retrospectively analyzed. Testosterone and other clinical factors at the start of docetaxel treatment were evaluated with respect to overall survival and progression-free survival. RESULTS: Of the 164 patients, 69 had high-volume tumors. The median prostatic-specific antigen was 27.0 ng/mL. The median testosterone was 13.0 ng/dL. The rates of bone and visceral metastases were 80.1% and 8.8%, respectively. For progression-free survival, testosterone ≥13 ng/dL was an independent prognostic factor only on univariate analysis (hazard ratio, 1.81; P = .0108). For overall survival, testosterone ≥ 1.3 ng/dL (hazard ratio, 3.37; P < .0001), high volume (hazard ratio, 3.06; P = .0009), and prostate-specific antigen ≥ 27.0 ng/mL (hazard ratio, 2.75; P = .0013) were independent prognostic factors on multivariate analysis. When assessing related clinical factors, higher serum testosterone was associated with visceral metastasis, high volume, and prostate-specific antigen. Based on three prognostic factors (testosterone, high volume, prostate-specific antigen), a risk classification was developed. The high-risk group (3 risk factors) showed a significantly shorter overall survival compared to the moderate-risk (2 risk factors) and low-risk (0-1 risk factor) groups (P < .0001). CONCLUSIONS: The present study identified higher serum testosterone (≥13 ng/dL) as a significant prognostic factor in castration-resistant prostate cancer patients treated with docetaxel therapy.

Factorization of Jet Cross Sections in Heavy-Ion Collisions.

We propose a new phenomenological approach to establish QCD factorization of jet cross sections in the heavy-ion environment. Starting from a factorization formalism in proton-proton collisions, we introduce medium modified jet functions to capture the leading interaction of jets with the hot and dense QCD medium. A global analysis using a Monte Carlo sampling approach is performed in order to reliably determine the new jet functions from the nuclear modification factor of inclusive jets at the LHC. We find that gluon jets are significantly more suppressed due to the presence of the medium than quark jets. In addition, we observe that the jet radius dependence is directly related to the relative suppression of quark and gluon jets. Our approach may help to improve the extraction of medium properties from data.

Population Pharmacokinetic Analyses for Arbekacin after Administration of ME1100 Inhalation Solution.

ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL = (weight/52.2)0.855·[(CLcrn-77)·0.0289 + 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data (r2 of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.

Current status and future perspective on preclinical pharmacokinetic and pharmacodynamic (PK/PD) analysis: Survey in Japan pharmaceutical manufacturers association (JPMA).

Preclinical pharmacokinetic/pharmacodynamic (PK/PD) analysis is an efficient tool for the translational research and proof of mechanism/concept in animals. The questionnaire survey on the practice of preclinical PK/PD analysis was conducted in the member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). According to the survey, 60% of companies conducted preclinical PK/PD analysis and its impact for drug development was different between each of the companies. The frequently analyzed therapeutic areas of preclinical PK/PD analysis were neurology, inflammation and metabolic disease, and those are different from the therapeutic area (infectious disease and oncology) in which PK/PD analysis was considered as effective by the present survey. Many companies which have used preclinical PK/PD analysis for the translation to human PK/PD and for the prediction of dose/regimen had good communication with other research & development (R&D) departments (e.g. pharmacology/clinical pharmacology). The increase in resources for preclinical PK/PD analysis including education was highly demanded. As a future perspective, the closer collaboration between pharmacokinetics scientists, pharmacologists, toxicologists and clinical pharmacologists and the increase in resources including upskilling and the comprehension of preclinical PK/PD analysis by the project team are considered to lead to efficient contributions to improve the success ratio of drug discovery and development.

Transient systolic anterior motion with junctional rhythm after mitral valve repair in the intensive care unit.

Systolic anterior motion (SAM) after mitral valve repair (MVR) can adversely affect hemodynamics due to exacerbation of left ventricular outflow tract obstruction and mitral regurgitation. Intraoperative transient SAM after MVR can usually be managed with hemodynamic maneuvers under continuous monitoring by transesophageal echocardiography (TEE). However, during postoperative intensive care management, transient SAM is seldom diagnosed and the start of treatment may be delayed. We present a case of transient SAM after MVR with abrupt deterioration due to junctional rhythm in the intensive care unit (ICU). TEE revealed that conversion from normal sinus rhythm into junctional rhythm induced the exacerbation of SAM. TEE was useful for identifying the etiology of unstable hemodynamics after cardiac surgery in the ICU, similar to its use in the operating room.

Perioperative posterior reversible encephalopathy syndrome in a patient with no history of hypertension: a case report.

BACKGROUND: Posterior reversible encephalopathy syndrome is characterized by reversible neurological symptoms with leukoencephalopathy detectable by computed tomography (CT) and magnetic resonance (MR) imaging. CASE PRESENTATION: We here present a patient with no history of hypertension who, after being transferred back to the ward after undergoing total hysterectomy under general anesthesia, had several seizures and lost consciousness. Posterior reversible encephalopathy syndrome was suspected on the basis of brain CT images and clinical findings. She was treated with respiratory support, sedative drugs, and anticonvulsants, and MR imaging confirmed a diagnosis of posterior reversible encephalopathy syndrome. She regained consciousness and responsiveness the following day. CONCLUSIONS: Clinically, posterior reversible encephalopathy syndrome resembles cerebral infarction or intracranial hemorrhage; MR imaging is useful for differentiating it from these conditions. Including this condition in the differential diagnosis and instituting appropriate treatment is important in minimizing the risk of development of irreversible neurological damage during the perioperative period.

Cold exposure and/or fasting modulate the relationship between sleep and body temperature rhythms in mice.

We assessed the relationship between core temperature (Tc) and sleep rhythms in mice, and examined the effects of ambient temperature and fasting. Tc, electroencephalograms (EEG), electromyograms (EMG), and spontaneous activity in male ICR mice (n=9) were measured by telemetry for 3 days under a 12:12h dark-light cycle. Mice were fed or fasted at an ambient temperature (Ta) of 27°C or 20°C for the final 30h of the experiment. The vigilance state was categorized into a wake state, rapid-eye movement (REM) sleep, and non-REM (NREM) sleep, and the total sleep time (TST) was assessed. Relationships between Tc and TST, NREM periods, and REM sleep were estimated using Pearson's correlation coefficient. During cold exposure, Tc decreased during the dark and light phases, and TST and the periods of NREM and REM sleep decreased during the dark phase. Throughout the fasting period, Tc also decreased during the dark and light phases. Furthermore, the decrease in Tc was augmented when fasting and cold were combined. TST and NREM sleep periods decreased in the light and dark phases, respectively, whereas REM sleep periods decreased in both phases. Negative linear correlations (r=-0.884 to -0.987) were observed between Tc and TST, NREM sleep periods, and REM sleep periods, except for Tc and REM sleep periods where fasting and cold conditions were combined. The correlations between sleep and Tc rhythms were well maintained during cold exposure and fasting. However, when cold and fasting were combined, REM sleep and Tc rhythms were desynchronized.

Prediction of clinical bacteriological efficacy of oral antibiotics using a mechanism-based pharmacokinetic-pharmacodynamics modeling.

The objective of this study was to predict the clinical bacteriological efficacy of antibiotics and to examine the pharmacodynamics (PD) characteristics of antibiotics against bacterial strains using a mechanism-based pharmacokinetic-pharmacodynamics (PK-PD) modeling developed on the basis of interaction between drug concentrations and antibacterial activities. Dynamic PD parameters (epsilon, gamma, EC50) and growth rate of organisms (lambda) were obtained from in vitro time-kill profile data of oral antibiotics, tebipenem pivoxil (TBPM-PI) and cefditoren pivoxil (CDTR-PI) against Streptococcus pneumoniae or Haemophilus influenzae. PD characteristics of both drugs against S. pneumoniae or H. influenzae were examined, which indicated TBPM was concentration-dependent as well as time-dependent, and CDTR was mainly time-dependent to exhibit their bactericidal activities. Next, we simulated TBPM and CDTR concentrations in plasma after oral administration according to the dosage regimen of each drug specified in package insert, using population pharmacokinetic parameters of both drugs in pediatric patients with infections. In addition, changes in viable in vivo bacterial counts in humans were simulated using dynamic PD parameters and mean plasma concentrations of each drug. As a result, simulated profile of viable counts of S. pneumoniae and H. influenzae were well corresponding to the bacteriological efficacy results in clinical double-blinded comparative study of TBPM-PI and CDTR-PI in oral administration to pediatric patients with acute otitis media. As mentioned in the above, it was considered to be possible to clarify the PD characteristics of TBPM and CDTR against each bacterial strain using the mechanism-based PK-PD model developed on the basis of interaction between drug concentrations and antibacterial activities, and to estimate the clinical bacteriological efficacy of those drugs.