Evidence for d-wave superconductivity of infinite-layer nickelates from low-energy electrodynamics.

The discovery of superconductivity in infinite-layer nickelates established another category of unconventional superconductors that shares structural and electronic similarities with cuprates. However, key issues of the superconducting pairing symmetry, gap amplitude and superconducting fluctuations are yet to be addressed. Here we utilize static and ultrafast terahertz spectroscopy to address these. We demonstrate that the equilibrium terahertz conductivity and non-equilibrium terahertz responses of an optimally Sr-doped nickelate film (superconducting transition temperature of Tc = 17 K) are in line with the electrodynamics of d-wave superconductivity in the dirty limit. The gap-to-Tc ratio (2Δ/kBTc) is found to be 3.4, indicating that the superconductivity falls in the weak coupling regime. In addition, we observed substantial superconducting fluctuations near Tc that do not extend into the deep normal state as the optimally hole-doped cuprates do. Our results support a d-wave system that closely resembles the electron-doped cuprates.

Linear-in-temperature resistivity for optimally superconducting (Nd,Sr)NiO2.

The occurrence of superconductivity in proximity to various strongly correlated phases of matter has drawn extensive focus on their normal state properties, to develop an understanding of the state from which superconductivity emerges1-4. The recent finding of superconductivity in layered nickelates raises similar interests5-8. However, transport measurements of doped infinite-layer nickelate thin films have been hampered by materials limitations of these metastable compounds: in particular, a high density of extended defects9-11. Here, by moving to a substrate (LaAlO3)0.3(Sr2TaAlO6)0.7 that better stabilizes the growth and reduction conditions, we can synthesize the doping series of Nd1-xSrxNiO2 essentially free from extended defects. In their absence, the normal state resistivity shows a low-temperature upturn in the underdoped regime, linear behaviour near optimal doping and quadratic temperature dependence for overdoping. This is phenomenologically similar to the copper oxides2,12 despite key distinctions-namely, the absence of an insulating parent compound5,6,9,10, multiband electronic structure13,14 and a Mott-Hubbard orbital alignment rather than the charge-transfer insulator of the copper oxides15,16. We further observe an enhancement of superconductivity, both in terms of transition temperature and range of doping. These results indicate a convergence in the electronic properties of both superconducting families as the scale of disorder in the nickelates is reduced.

Comprehensive Analysis of Epstein-Barr Virus LMP2A-Specific CD8+ and CD4+ T Cell Responses Restricted to Each HLA Class I and II Allotype Within an Individual.

Latent membrane protein 2A (LMP2A), a latent Ag commonly expressed in Epstein-Barr virus (EBV)-infected host cells, is a target for adoptive T cell therapy in EBV-associated malignancies. To define whether individual human leukocyte antigen (HLA) allotypes are used preferentially in EBV-specific T lymphocyte responses, LMP2A-specific CD8+ and CD4+ T cell responses in 50 healthy donors were analyzed by ELISPOT assay using artificial Ag-presenting cells expressing a single allotype. CD8+ T cell responses were significantly higher than CD4+ T cell responses. CD8+ T cell responses were ranked from highest to lowest in the order HLA-A, HLA-B, and HLA-C loci, and CD4+ T cell responses were ranked in the order HLA-DR, HLA-DP, and HLA-DQ loci. Among the 32 HLA class I and 56 HLA class II allotypes, 6 HLA-A, 7 HLA-B, 5 HLA-C, 10 HLA-DR, 2 HLA-DQ, and 2 HLA-DP allotypes showed T cell responses higher than 50 spot-forming cells (SFCs)/5×105 CD8+ or CD4+ T cells. Twenty-nine donors (58%) showed a high T cell response to at least one allotype of HLA class I or class II, and 4 donors (8%) had a high response to both HLA class I and class II allotypes. Interestingly, we observed an inverse correlation between the proportion of LMP2A-specific T cell responses and the frequency of HLA class I and II allotypes. These data demonstrate the allele dominance of LMP2A-specific T cell responses among HLA allotypes and their intra-individual dominance in response to only a few allotypes in an individual, which may provide useful information for genetic, pathogenic, and immunotherapeutic approaches to EBV-associated diseases.

Comprehensive analysis of mycobacterium tuberculosis antigen-specific CD4+ T cell responses restricted by single HLA class II allotype in an individual.

Mycobacterium tuberculosis infection is generally asymptomatic as latent tuberculosis, but it is still known as the world's leading bacterial cause of death. The diagnosis of latent tuberculosis infection relies on the evidence of cellular immunity to mycobacterial antigens. Since the association between HLA class II and tuberculosis infection has been reported in several population groups, a detailed study on the CD4+ T cell response to major tuberculosis antigens is needed. To elucidate which HLA class II allotypes in an individual are preferentially used in tuberculosis, CD4+ T cells specific to TB10.4, Ag85b, ESAT-6, and CFP-10 of Mycobacterium tuberculosis antigens were analyzed comprehensively. A total of 33 healthy donors were analyzed by ex vivo and cultured ELISPOT using panels of artificial antigen-presenting cells expressing a single HLA class II allotype. The CD4+ T cell responses were increased by an average of 39-fold in cultured ELISPOT compared with ex vivo ELISPOT. In ex vivo and cultured ELISPOT, CD4+ T cell responses showed significantly higher by HLA-DR than those of HLA-DQ and HLA-DP locus. In cultured ELISPOT, 9 HLA-DR allotypes, 4 HLA-DQ allotypes, and 3 HLA-DP allotypes showed positive CD4+ T cell responses. Among ten donors with positive CD4+ T cell responses when tested for mixed Mycobacterium tuberculosis antigens, seven donors were positive for only a single allotype, and three were positive for two allotypes in an individual. However, only one allotype was used for a single antigen-specific response when a single tuberculosis antigen was used individually. These results on the distribution of HLA class II allotypes showing high CD4+ T-cell responses to Mycobacterium tuberculosis antigens and the intra-individual allotype dominance will provide valuable information for understanding the immunobiology and immunogenetics of tuberculosis, which can contribute to the development of more effective vaccines.

Comprehensive Analysis of CD4+ T Cell Response Cross-Reactive to SARS-CoV-2 Antigens at the Single Allele Level of HLA Class II.

Common human coronaviruses have been circulating undiagnosed worldwide. These common human coronaviruses share partial sequence homology with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); therefore, T cells specific to human coronaviruses are also cross-reactive with SARS-CoV-2 antigens. Herein, we defined CD4+ T cell responses that were cross-reactive with SARS-CoV-2 antigens in blood collected in 2016-2018 from healthy donors at the single allele level using artificial antigen-presenting cells (aAPC) expressing a single HLA class II allotype. We assessed the allotype-restricted responses in the 42 individuals using the aAPCs matched 22 HLA-DR alleles, 19 HLA-DQ alleles, and 13 HLA-DP alleles. The response restricted by the HLA-DR locus showed the highest magnitude, and that by HLA-DP locus was higher than that by HLA-DQ locus. Since two alleles of HLA-DR, -DQ, and -DP loci are expressed co-dominantly in an individual, six different HLA class II allotypes can be used to the cross-reactive T cell response. Of the 16 individuals who showed a dominant T cell response, five, one, and ten showed a dominant response by a single allotype of HLA-DR, -DQ, and -DP, respectively. The single allotype-restricted T cells responded to only one antigen in the five individuals and all the spike, membrane, and nucleocapsid proteins in the six individuals. In individuals heterozygous for the HLA-DPA and HLA-DPB loci, four combinations of HLA-DP can be expressed, but only one combination showed a dominant response. These findings demonstrate that cross-reactive T cells to SARS-CoV-2 respond with single-allotype dominance.

Large-Scale Assembly of Peptide-Based Hierarchical Nanostructures and Their Antiferroelectric Properties.

An effective strategy is developed to create peptide-based hierarchical nanostructures through the meniscus-driven self-assembly in a large area and fabricate antiferroelectric devices based on these nanostructures for the first time. The diphenylalanine hierarchical nanostructures (FF-HNs) are self-assembled by vertically pulling a substrate from a diphenylalanine (FF) solution dissolved in a miscible solvent under precisely controlled conditions. Owing to the unique structural properties of FF nanostructures, including high crystallinity and α-helix structures, FF-HNs possess a net electrical dipole moment, which can be switched in an external electric field. The mass production of antiferroelectric devices based on FF-HNs can be successfully achieved by means of this biomimetic assembly technique. The devices show an evident antiferroelectric to ferroelectric transition under dark conditions, while the ferroelectricity is found to be tunable by light. Notably, it is discovered that the modulation of antiferroelectric behaviors of FF-HNs under glutaraldehyde exposure is due to the FF molecules that are transformed into cyclophenylalanine by glutaraldehyde. This work provides a stepping stone toward the mass production of self-assembled hierarchical nanostructures based on biomolecules as well as the mass fabrication of electronic devices based on biomolecular nanostructures for practical applications.

An allometric pharmacokinetic model and minimum effective analgesic concentration of fentanyl in patients undergoing major abdominal surgery.

BACKGROUND: We aimed to characterise the population pharmacokinetics of fentanyl in adults and to determine the minimum effective concentration (MEC) and minimum effective analgesic concentration (MEAC) of i.v. fentanyl in patients after major abdominal open surgery. METHODS: In the pharmacokinetic study, subjects received an intravenous bolus of fentanyl 100 µg during operation, and arterial blood was sampled at pre-set intervals. In addition, data from previously published fentanyl pharmacokinetic studies were incorporated to build a pharmacokinetic model. In the MEAC study, subjects were asked to rate their pain every 10 min using a VAS (0=no pain, 10=most severe pain) in the PACU. The first blood sample was obtained when wound pain was rated as ≥3 at rest or ≥5 during compression. Then, fentanyl 50 µg was administered every 10 min until the pain intensity had decreased to <3 at rest and <5 during compression, at which point the second blood was sampled and the first MEAC of fentanyl was measured. The same procedure was repeated to obtain a third sample (MEC) and a fourth sample (second MEAC). RESULTS: In the population pharmacokinetic study (n=95), the plasma concentration of fentanyl over time was well-described by the three-compartment mammillary model using an allometric expression. The V1, V2, V3, Cl, Q1, and Q2 of a 70 kg subject were 10.1, 26.5, 206 L, 0.704, 2.38, and 1.49 L min-1, respectively. In the MEAC study (n=30), the median (inter-quartile range) MEC and MEAC were 0.72 (0.58-1.05) ng ml-1, and 0.99 (0.76-1.28) ng ml-1, respectively. CONCLUSION: These results provide a scientific basis for the use of fentanyl for acute postoperative pain management in surgical patients. CLINICAL TRIAL REGISTRATION: KCT0003273 (http://cris.nih.go.kr).

Performance of the nasal photoplethysmographic index as an analgesic index during surgery under general anaesthesia.

In a previous study, we developed a new analgesic index using nasal photoplethysmography (nasal photoplethysmographic index, NPI) and showed that the NPI was superior to the surgical pleth index (SPI) in distinguishing pain above numerical rating scale 3. Because the NPI was developed using data obtained from conscious patients with pain, we evaluated the performance of NPI in comparison with the SPI and the analgesia nociception index (ANI) in patients under general anaesthesia with target-controlled infusion of propofol and remifentanil. The time of nociception occurrence was defined as when the signs of inadequate anaesthesia occurred. The median values of NPI, SPI, and ANI for 1 minute from the time of the sign of inadequate anaesthesia were determined as the value of each analgesic index that represents inadequate anaesthesia. The time of no nociception was determined as 2 minutes before the onset of skin incision, and the median value for 1 minute from that time was defined as the baseline value. In total, 81 patients were included in the analysis. NPI showed good performance in distinguishing inadequate anaesthesia during propofol-remifentanil based general anaesthesia. NPI had the highest value in terms of area under the receiver operating characteristic curve, albeit without statistical significance (NPI: 0.733, SPI: 0.722, ANI: 0.668). The coefficient of variations of baseline values of NPI, SPI, and ANI were 27.5, 47.2, and 26.1, respectively. Thus, the NPI was effective for detecting inadequate anaesthesia, showing similar performance with both indices and less baseline inter-individual variability than the SPI.

Recent Developments and Prospects of M13- Bacteriophage Based Piezoelectric Energy Harvesting Devices.

Recently, biocompatible energy harvesting devices have received a great deal of attention for biomedical applications. Among various biomaterials, viruses are expected to be very promising biomaterials for the fabrication of functional devices due to their unique characteristics. While other natural biomaterials have limitations in mass-production, low piezoelectric properties, and surface modification, M13 bacteriophages (phages), which is one type of virus, are likely to overcome these issues with their mass-amplification, self-assembled structure, and genetic modification. Based on these advantages, many researchers have started to develop virus-based energy harvesting devices exhibiting superior properties to previous biomaterial-based devices. To enhance the power of these devices, researchers have tried to modify the surface properties of M13 phages, form biomimetic hierarchical structures, control the dipole alignments, and more. These methods for fabricating virus-based energy harvesting devices can form a powerful strategy to develop high-performance biocompatible energy devices for a wide range of practical applications in the future. In this review, we discuss all these issues in detail.

Comprehensive Analysis of CD4+ T Cell Responses to CMV pp65 Antigen Restricted by Single HLA-DR, -DQ, and -DP Allotype Within an Individual.

Within an individual, six different HLA class II heterodimers are expressed co-dominantly by two alleles of HLA-DR, -DQ, and -DP loci. However, it remained unclear which HLA allotypes were used in T cell responses to a given antigen. For the measurement of the CD4+ T cell responses restricted by a single HLA allotype, we established a panel of artificial antigen-presenting cells (aAPCs) expressing each single HLA allele of 20 HLA-DRB1, 16 HLA-DQ, and 13 HLA-DP alleles. CD4+ T cell responses to cytomegalovirus (CMV) pp65 restricted by single HLA class II allotype defined in 45 healthy donors. The average magnitude of CD4+ T cell responses by HLA-DR allotypes was higher than HLA-DQ and HLA-DP allotypes. CD4+ T cell responses by DRA*01:01/DRB1*04:06, DQA1*01:02/DQB1*06:02, DPA1*02:02/DPB1*05:01 were higher among the other alleles in each HLA-DR, -DQ, and -DP locus. Interestingly, the frequencies of HLA-DR alleles and the positivity of specific allotypes showed an inverse correlation. One allotype within individuals is dominantly used in CD4+ T cell response in 49% of donors, and two allotypes showed that in 7% of donors, and any positive response was detected in 44% of donors. Even if one individual had several dominant alleles, CD4+ T cell responses tended to be restricted by only one of them. Furthermore, CD8+ and CD4+ T cell responses by HLA class I and class II were correlated. Our results demonstrate that the CD4+ T cell preferentially use a few dominant HLA class II allotypes within individuals, similar to CD8+ T cell response to CMV pp65.

Evaluation of Surgical Pleth Index and Analgesia Nociception Index as surrogate pain measures in conscious postoperative patients: an observational study.

We evaluated the performance of the Surgical Plethysmographic Index (SPI) and the Analgesia Nociception Index (ANI) as surrogate pain measures and determined their respective cut-off values for detecting pain in conscious postoperative patients. In total, 192 patients after elective surgery were enrolled. Baseline SPI and ANI data were acquired for 10 min in the operating room prior to surgery when the patients rated their pain as 0 on the numerical rating scale (NRS). Upon arrival in the post-anaesthesia care unit (PACU) after surgery, SPI and ANI data were recorded for 10 min. The means of the recorded data at OR and PACU were defined as the values representing baseline and postoperative pain, respectively. SPI and ANI data obtained from 189 patients were analysed, who were anesthetized with propofol (n = 149) or sevoflurane (n = 40). Remifentanil was continuously infused intraoperatively in all patients. The values of SPI and ANI were significantly different in conscious patients without (NRS = 0) and with pain (NRS > 0). The areas under the receiver operating curves for SPI and ANI were 0.73 (P < 0.0001) and 0.67 (P < 0.0001), respectively. The cut-off values for SPI and ANI in predicting postoperative pain were 44 (sensitivity: 84%, specificity: 53%) and 63 (sensitivity: 52%, specificity: 82%), respectively, which are different from those suggested by their respective manufacturers for use in intraoperative state under general anaesthesia. The cut-off values of SPI and ANI for detecting pain were similar regardless of the type of anesthesia.

Changes in plasma volume before and after major abdominal surgery following stroke volume variation-guided fluid therapy: a randomized controlled trial.

BACKGROUND: The aim of intraoperative fluid therapy is to avoid both hypovolemia and hypervolemia; however, the patient's exact volume status is difficult to determine during surgery. Fluid optimization guided by stroke volume variation (SVV) has been widely used in patients undergoing major open abdominal surgery. The aim of this study was to evaluate the changes in plasma volume before and after surgery following SVV-guided fluid therapy. METHODS: Patients were randomly allocated into one of two groups according to the SVV criteria for fluid administration during surgery. In the fixed SVV fluid strategy group, fluid was administered to maintain the SVV below 13%. In the individual SVV group, individual SVV values of each patient were maintained until the end of surgery. Plasma volume, body weight, and extracellular water (ECW) were measured before and after surgery. Plasma volume was estimated using the indocyanine green dilution technique. RESULTS: A total of 118 patients were included. Median (25-75%) plasma volumes in the preoperative and postoperative period were 2.46 (2.20-2.88) L and 2.69 (2.33-3.12) L for the fixed SVV group (N.=57, P=0.133), respectively, and 2.56 (2.23-2.90) L and 2.89 (2.48-3.19) L for the individual SVV group (N.=61, P<0.001), respectively. CONCLUSIONS: Fluid administration during surgery to maintain SVV below 13% was effective for maintaining the preoperative plasma volume until the end of surgery in patients undergoing major open stomach or colorectal surgery. This result supports the validity of SVV-guided fluid therapy, which maintains the SVV value below 13%, in terms of maintaining patient volume status.

Population-based volume kinetics of crystalloids and colloids in healthy volunteers.

We characterized the volume kinetics of crystalloid solutions (Ringer's lactate solution and 5% dextrose water) and colloid solutions (6% tetrastarch and 10% pentastarch) by nonlinear mixed-effects modeling in healthy volunteers. We also assessed whether the bioelectrical impedance analysis parameters are significant covariates for volume kinetic parameters. Twelve male volunteers were randomly allocated to four groups, and each group received the four fluid solutions in specified sequences, separated by 1-week intervals to avoid any carryover effects. Volunteers received 40 ml/kg Ringer's lactate solution, 20 ml/kg 5% dextrose water, 1000 ml 6% tetrastarch, and 1000 ml 10% pentastarch over 1 h. Arterial blood samples were collected to measure the hemoglobin concentration at different time points. Bioelectrical impedance spectroscopy (BIS, INBODY S10, InBody CO., LTD, Seoul, Korea) was also carried out at preset time points. In total, 671 hemoglobin-derived plasma dilution data points were used to determine the volume kinetic characteristics of each fluid. The changes in plasma dilution induced by administration of crystalloid and colloid solutions were well-described by the two-volume and one-volume models, respectively. Extracellular water was a significant covariate for the peripheral volume of distribution at baseline in the volume kinetic model of Ringer's lactate solution. When the same amount was administered, the colloid solutions had ~4 times more plasma expansion effect than did the crystalloid solutions. Starches with larger molecular weights maintained the volume expansion effect longer than those with smaller molecular weights.

Effects of depth of neuromuscular block on postoperative pain during laparoscopic gastrectomy: A randomised controlled trial.

BACKGROUND: Evidence on whether the use of deep neuromuscular block (NMB) influences postoperative pain after laparoscopic surgery is limited, and existing studies have shown conflicting results. We studied the effect of the depth of NMB during laparoscopic gastrectomy on postoperative pain. OBJECTIVE: The aim of this study was to evaluate the effect of depth of NMB during laparoscopic gastrectomy on postoperative pain by allocating patients randomly to either deep or moderate NMB with a standard-pressure pneumoperitoneum. DESIGN: A randomised, controlled, double-blind study. SETTING: A university-affiliated hospital. PARTICIPANTS: One hundred patients. INTERVENTIONS: Patients were allocated randomly to receive either deep (posttetanic count 1 to 2) or moderate (train-of-four count 1 to 2) levels of NMB. Following surgery, the patients were asked to rate their pain every 10 min using a visual analogue scale (VAS) (0 = no pain, 10 = most severe pain) in the postanaesthesia care unit (PACU). Patients received intravenous oxycodone, 2 mg every 10 min, until the pain intensity (VAS) had decreased to less than 3 at rest and less than 5 on wound compression, at which point the minimum effective analgesia dose (MEAD) of oxycodone was determined. MAIN OUTCOME MEASURES: The primary endpoint was the MEAD of oxycodone. Secondary endpoints included area under the curve of VAS for wound pain, VAS scores for wound and shoulder pain at 6 and 24 h after the end of surgery, rescue analgesics, a five-point surgical rating scale, Rhodes index of nausea vomiting retching at 6 and 24 h after the end of surgery and duration of pneumoperitoneum. RESULTS: The median value for the MEAD of oxycodone was 8 mg in both groups. Area under the curves of VAS over time were similar in both groups. Variables associated with postoperative pain including mean VAS at PACU and frequency of rescue analgesics in the ward did not differ significantly between the two groups. The duration of pneumoperitoneum was a significant variable in determining the MEAD of oxycodone (linear regression, R = 0.07, P = 0.008). The number of patients who reached the acceptable surgical score was not significantly different between the two groups. However, the moderate NMB group did have a significantly higher proportion of cases that required additional muscle relaxants (P < 0.001). CONCLUSION: Deep, compared with moderate, NMB did not significantly reduce the MEAD of oxycodone administered in the PACU. The duration of pneumoperitoneum was positively correlated with the MEAD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03266419.

Predictive performance of a new pharmacokinetic model for propofol in underweight patients during target-controlled infusion.

BACKGROUND: In a previous study, the modified Marsh and Schnider models respectively showed negatively- and positively-biased predictions in underweight patients. To overcome this drawback, we developed a new pharmacokinetic propofol model-the Choi model-for use in underweight patients. In the present study, we evaluated the predictive performance of the Choi model. METHODS: Twenty underweight patients undergoing elective surgery received propofol via TCI using the Choi model. The target effect-site concentrations (Ces) of propofol were 2.5, 3, 3.5, 4, 4.5, and 2 µg/mL. Arterial blood samples were obtained at least 10 minutes after achieving pseudo-steady-state. Predicted propofol concentrations with the modified Marsh, Schnider, and Eleveld pharmacokinetic models were obtained by simulation (Asan pump, version 2.1.3; Bionet Co. Ltd., Seoul, Korea). The predictive performance of each model was assessed by calculation of four parameters: inaccuracy, divergence, bias, and wobble. RESULTS: A total of 119 plasma samples were used to determine the predictive performance of the Choi model. Our evaluation showed that the pooled median (95% CI) bias and inaccuracy were 4.0 (-4.2 to 12.2) and 23.9 (17.6-30.3), respectively. The pooled biases and inaccuracies of the modified Marsh, Schnider, and Eleveld models were clinically acceptable. However, the modified Marsh and Eleveld models consistently produced negatively biased predictions in underweight patients. In particular, the Schnider model showed greater inaccuracy at a target Ce ≥ 3 µg/mL. CONCLUSION: The new propofol pharmacokinetic model (the Choi model) developed for underweight patient showed adequate performance for clinical use.

Population-based volume kinetics of Ringer's lactate solution in patients undergoing open gastrectomy.

In order to maintain stable blood pressure and heart rate during surgery, anesthesiologists need to administer the appropriate amount of fluid with appropriate fluid type to the patient, then quantifying how fluid is distributed and eliminated from the body is useful for establishing a fluid administration strategy. In this study we characterized the volume kinetics of Ringer's lactate solution in patients undergoing open gastrectomy. When propofol and remifentanil reached a pseudosteady state at the target concentration and blood pressure was stabilized following surgical stimulation, enrolled patients were administered 1000 mL of Ringer's lactate solution for 20 min, followed by continuous infusion at a rate of 6 mL/kg/h until the time of the last blood collection for volume kinetic analysis. Arterial blood samples were collected to measure the hemoglobin concentration at different time points. The change in hemoglobin-derived plasma dilution induced by the administration of Ringer's lactate solution was evaluated by nonlinear mixed effects modeling. Three hundred and twenty-three plasma dilution data points from 27 patients were used to determine the pharmacokinetic characteristics of Ringer's lactate solution. A two-volume model best described the pharmacokinetics of Ringer's lactate solution. The mean arterial pressure (MAP) and body weight (WT) were significant covariates for the elimination clearance (kr) and central volume of distribution at baseline (Vc0), respectively. The parameter estimates were as follows: kr (mL/min) = 124 + (MAP/70)14.2, Vc0 (mL) = 0.95 + 3440 × (WT/63), Vt0 (mL) = 2730, and kt (mL/min) = 181. A higher MAP was associated with a greater elimination clearance and, consequently, less water accumulation in the interstitium. As body weight increases, volume expansion in the blood vessels increases.

Accuracy assessment of a PION TCI pump based on international standards.

BACKGROUND: Inaccuracies associated with target-controlled infusion (TCI) delivery systems are attributable to both software and hardware issues, as well as pharmacokinetic variability. However, little is known about the inaccuracy of the syringe pump operating in TCI mode. This study aimed to evaluate the accuracy of the TCI pump based on international standards. METHODS: A test apparatus for accuracy evaluation of a syringe pump (PION TCI®, Bionet Co. Ltd.) was designed to apply the gravimetric method. Pump accuracy was evaluated in terms of deviation defined by the following equation: infusion rate deviation (%) = (Ratemea - Rateest ) / Rateest × 100, where Ratemea is the infusion rate (ml/h) as measured by the gravimetric system, and Rateest is the infusion rate (ml/h) as estimated by the pump. An infusion rate representing TCI mode was determined from previous clinical trial data which evaluated the predictive performance of the pharmacokinetic model. The PION TCI pump used in that clinical trial was used to evaluate accuracy of the syringe pump. The distribution of infusion rates obtained from the clinical trial was calculated, and the median value of the distribution was determined as the representative value. RESULTS: The representative infusion rate representing TCI mode was 31 ml/h, at which the infusion rate deviation was 4.5 ± 1.6%. CONCLUSIONS: The inaccuracy of the syringe pump contributing to TCI system inaccuracy is insignificant.

Influence of surface tension-driven network parameters on backflow strength.

Surface tension-driven flow is widely used, owing to its spontaneous motion, in microfluidic devices with single channel structures. However, when multiple channels are used, unwanted backflow often occurs. This prevents precise and sophisticated solution flow, but has been rarely characterized. We hypothesize that, with an analytical model, the parameters that influence backflow can be systematically characterized to minimize the backflow. In a microfluidic network, inlet menisci and channels are modeled as variable pressure sources and fluidic conductors, respectively. Through the model and experiment, the influence of each network element on the backflow strength is studied. Backflow strength is affected by the interplay of multiple inlet-channel elements. With the decrease (increase) of the fluidic channel conductance (inlet size), the backflow pressure of the corresponding inlet decreases. On the other hand, backflow volume reaches its peak value during the radius change of the corresponding inlet. In networks consisting of five inlet-channel elements, backflow pressure decreases with increasing step number. Our results provide the foundations for microfluidic networks driven by the Laplace pressure of inlet menisci.

Pulsatile plasma filtration and cell-free DNA amplification using a water-head-driven point-of-care testing chip.

We demonstrate a microfiltration chip that separates blood plasma by using water-head-driven pulsatile pressures rather than any external equipment and use it for on-chip amplification of nucleic acids. The chip generates pulsatile pressures to significantly reduce filter clogging without hemolysis, and consists of an oscillator, a plasma-extraction pump, and filter units. The oscillator autonomously converts constant water-head pressure to pulsatile pressure, and the pump uses the pulsatile pressure to extract plasma through the filter. Because the pulsatile pressure can periodically clear blood cells from the filter surface, filter clogging can be effectively reduced. In this way, we achieve plasma extraction with 100% purity and 90% plasma recovery at 15% hematocrit. During a 10 min period, the volume of plasma extracted was 43 µL out of a 243 µL extraction volume at 15% hematocrit. We also studied the influence of the pore size and diameter of the filter, blood loading volume, oscillation period, and hematocrit level on the filtration performance. To demonstrate the utility of our chip for point-of-care testing (POCT) applications, we successfully implemented on-chip amplification of a nucleic acid (miDNA21) in plasma filtered from blood. We expect our chip to be useful not only for POCT applications but also for other bench-top analysis tools using blood plasma.

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

BACKGROUND: Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. METHODS: The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. FINDINGS: Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI -6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. INTERPRETATION: A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. FUNDING: National Institutes of Health and Cancer Center Support.