The bone morphogenetic protein (BMP) signaling pathways have important roles in embryonic development and cellular homeostasis, with aberrant BMP signaling resulting in a broad spectrum of human ...disease. We report that BMPs unexpectedly signal through the canonical transforming growth factor β (TGF‐β)‐responsive Smad2 and Smad3. BMP‐induced Smad2/3 signaling occurs preferentially in embryonic cells and transformed cells. BMPs signal to Smad2/3 by stimulating complex formation between the BMP‐binding TGF‐β superfamily receptors, activin receptor‐like kinase (ALK)3/6, and the Smad2/3 phosphorylating receptors ALK5/7. BMP signaling through Smad2 mediates, in part, dorsoventral axis patterning in zebrafish embryos, whereas BMP signaling through Smad3 facilitates cancer cell invasion. Consistent with increased BMP‐mediated Smad2/3 signaling during cancer progression, Smad1/5 and Smad 2/3 signaling converge in human cancer specimens. Thus, the signaling mechanisms used by BMPs and TGF‐β superfamily receptors are broader than previously appreciated.—Holtzhausen, A., Golzio, C., How, T., Lee, Y.‐H., Schiemann, W. P., Katsanis, N., Blobe, G. C. Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development. FASEB J. 28, 1248–1267 (2014). www.fasebj.org
This paper proposes a new algorithm for detecting suicide notes using sentiment analysis. As suicides increase nowadays, it is important to detect the suicide signs before the actual suicides are ...committed. Detecting suicide signs is not so easy, because suicide notes are usually short. This study proposes a modified algorithm of sentiment analysis which is based on the probability of positive sentiments (PPS), not on the categorical classifications. The original BERT model is revised so that the model calculates the PPS values for each sentence. A total of 8 corpora are constructed, among which 4 are the corpora of suicide notes, and the others are novels. For each sentence in the corpora, the PPS values are calculated using the revised BERT model. Then, the distributions of PPSs are statistically analyzed with Interquartile Range (IQR). The suicide notes are distinguished with more than 30 IQR values. In the experiments with the corpora of suicide notes and ordinary texts, the developed method achieves about 86% of accuracy. The proposed algorithm can make use of the sentiment properties of suicide notes, and it is effective not only for large-size corpora but also for small-size suicide notes. KCI Citation Count: 0
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.
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.
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).
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.
These results provide a scientific basis for the use of fentanyl for acute postoperative pain management in surgical patients.
KCT0003273 (http://cris.nih.go.kr).
Abstract
This study characterized focused tones in Mandarin Chinese through a production experiment using phone number
strings. The results revealed that, although phonation cues had little effect on ...any focused tone, prosodic cues exhibited various
patterns of distribution. Duration played an important role for each focused tone, but intensity had a relatively less salient
role. Among pitch-related parameters, the raising of pitch register was an important cue when a level tone (tone 1) was focused. By
contrast, due to the interaction between tone and intonation, absolute slope and pitch range had less effect on tone 1 focus.
These cues, however, were prominent when contour tones (tones 2 and 4) were in focus. Unlike other focused tones that raised
pitch, tone 3 focus exhibited the opposite pattern, lowering its pitch target. In the aggregation of all focused tones, it was
found that only primarily pitch-related parameters were selected as the main variables discriminating one from another. The
results of this study, therefore, suggest that the prosodic marking of focus is not uniform, even within a single language, but
clearly differs by tone type. Accordingly, prosodic marking of focus should be considered multimodal in a tonal language.
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.
Aims
This prospective study aimed to characterize the population pharmacokinetics of intravenous oxycodone and to determine the minimum effective concentration (MEC) and minimum effective analgesic ...concentration (MEAC) of oxycodone for major open intra‐abdominal surgery.
Methods
In the pharmacokinetic study, patients were administered intravenous oxycodone (0.1 mg kg−1), and arterial blood was sampled at pre‐set intervals. In the analgesic‐potency study, patients were administered intravenous oxycodone (0.1 mg kg−1) 30 min before the end of the surgery, were placed in the postoperative anaesthesia care unit (PACU), and were asked to rate their pain every 10 min using a visual analogue scale (0 = no pain, 10 = most severe pain). On the first occasion that wound pain at rest and during compression was rated as ≥3 or ≥5, respectively, the first blood sample was obtained to determine the MEC. A second blood sample was obtained after titration with 2 mg of oxycodone to yield wound pain <3 at rest and <5 during wound compression, and MEAC was determined. MEC and MEAC were determined again in each patient.
Results
In the population pharmacokinetic study (n = 54), oxycodone plasma concentration over time was well described by a three‐compartment mammillary model. Lean body mass and age were significant covariates for the volume of distribution and metabolic clearance of the pharmacokinetic model of oxycodone, respectively. The analgesic‐potency study (n = 50) showed that the median (95% CI) MEC and MEAC were 31.5 (19.2–42.8) and 74.1 (29.2–128.3) ng ml−1 (first measurements) and 63.4 (15.6–120.1) and 76.1 (32.9–132.7) ng ml−1 (second measurements), respectively.
Conclusions
In major intra‐abdominal open surgery, the MEAC and analgesic potency of oxycodone were 75 ng ml−1 and 60 ng ml−1, respectively.
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.
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.
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.
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