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Abstract The dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin (LNG) exhibits target‐mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP‐4 (sDPP‐4) and tissue transmembrane DPP‐4 (tDPP‐4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild‐type mice, but not in Dpp‐4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP‐4‐related renal reabsorption of LNG, we employed physiologically‐based pharmacokinetic (PBPK) modeling combined with a cluster Gauss–Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK–CGNM analysis using reported autoradiography data ([14C]‐LNG) in wild‐type and Dpp‐4‐deficient rats, DPP‐4‐specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP‐4 and the reabsorption clearance for LNG–DPP‐4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP‐4 expressions and in vitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high‐affinity probe for DPP‐4, comprehensive PBPK–CGNM analyses suggested a dynamic whole‐body distribution of DPP‐4, including its involvement in the renal reabsorption of LNG.

This paper proposes a new load-balancing method that supports Per-Connection Consistency (PCC) by leveraging ECMP with standardized routing protocols for operational simplicity. Load balancers must consistently deliver packets of a flow to one of the backend servers, even when the backend server pool changes. Achieving this property—PCC—is not a straightforward task and usually introduces additional complexity into networks, such as special packet forwarding mechanisms, synchronizing states across load balancers, and often complicated orchestration. Our approach, VRF-shadowing, achieves PCC on ECMP of routers without additional control plane systems by exploiting Segment Routing over IPv6 (SRv6). VRF-shadowing employs the daisy-chaining concept, achieving PCC in a stateless manner with a standardized SRv6-based Layer-3 VPN (L3VPN). VRF-shadowing is composed of two components: a minimal new feature for software of SRv6 routers and a new SRv6 End behavior at servers. We implemented the former in a commercial router and the latter in Linux and evaluated VRF-shadowing on an SRv6 L3VPN network built with only standardized routing protocols. The evaluation results demonstrate that VRF-shadowing preserves connections from being disrupted when the ECMP next-hops change. In the most severe scenario, VRF-shadowing reduced the failed HTTP requests rate from 77% to 0.7% compared to traditional ECMP.

Abstract Background Postoperative delirium in intensive care is common and associated with mortality, cognitive impairment, prolonged hospital stays and high costs. We evaluate whether a nurse-led orientation program could reduce the incidence of delirium in the intensive care unit after cardiovascular surgery. Methods In this retrospective cohort study, we enrolled patients admitted to the intensive care unit for planned cardiovascular surgery between January 2020 and December 2021. A nurse-led orientation program based on a preoperative visit was routinely introduced from January 2021. We assessed the association between these visits and postoperative delirium in the intensive care unit. We also assessed predictors of postoperative delirium with baseline and intraoperative characteristics. Results Among 253 patients with planned cardiovascular surgery, 128 (50.6%) received preoperative visits. Valve surgery comprised 44.7%, coronary surgery 31.6%, and aortic surgery 20.9%. Cardiopulmonary bypass use and transcatheter surgery were 60.5% and 12.3%, respectively. Incidence of delirium was lower in patients that received preoperative visits, and median hospital stay was shorter than in those without visits (18 patients [14.1%] vs 34 patients [27.2%], P

Many studies have confirmed the memory enhancement effect of production, generation and elaboration which can be effective after only one encoding. It is also known that greater memory enhancement effects can be obtained by combining multiple memory strategies during encoding. This study aimed to investigate whether the combination of production and self-generated elaboration enhances memory performance compared with production or generation alone. A total of 23 undergraduate and graduate students participated in this study. In the functional magnetic resonance imaging analysis, we explored the neural representation of remembering information after production and self-generated elaboration strategy. We set four encoding strategy conditions: (1) Read Silent (read without production), (2) Read Aloud (only production), (3) Add Silent (self-generated elaboration without production), (4) Add Aloud (production and self-generated elaboration). The retrieval performance and brain activity while retrieving the learned sentences after a one-week delay were examined. The behavioral results showed that the highest memory performance was for sentences encoded in Add Aloud. The interaction between production and self-generated elaboration was statistically significant. These results suggest that the memory enhancement effect of combining production and self-generated elaboration is not a simple addition nor synergistic facilitation effect. The imaging results showed that the following areas were related to the retrieval of the target encoded in the add aloud condition: the area related to integration of internal and external information (precuneus), area related to information rich stimuli (lateral occipital lobe), area related to self-involvement and inference of others' feelings (MPFC), area related to seen imagery (retrosplenial region) and area related to adjustment of movement (cerebellum). These results suggest that with an encoding strategy that combines production and self-generated elaboration, integrated auditory input of vocalizations and generated images, visual images of the scene, self-relevance, inference of other's feeling, movement by moving mouth are stored with the target and enhanced memory performance of AA.

In recent years, with the rapid growth of Social Networking Service (SNS), Information-Centric Networking (ICN) has been emerged as a promising network architecture for mitigating the traffic generated by SNS users. To fully utilize potential of ICN as a sort of the cache network, we have to carefully design the caching strategy and the cache-replacement policy while considering both of features of social network among SNS users and those of cache network. Therefore, in this paper, we assume that ICN is introduced as a content distribution infrastructure for SNS, and extensively analyze the characteristics of the socially-aware ICN. In particular, we focus on the influential user called influencer, which is one of typical features of social networks, and investigate the effect of the selection of influential users and their ratio on the content caching in ICNs. Our key findings are summarized as follows. First, the effectiveness of the content caching is dominated by the centrality measures to determine influential users. Second, on determining influential users, it is enough to sample at most 30% of the social network rather than its entire structure. Third, to gain the benefit of the content caching, we have to carefully select the ratio of influential users on the social network whose degree distribution follows power-law.

Abstract Lung to finger circulation time (LFCT) has been used to estimate cardiac function. We developed a new LFCT measurement device using a laser sensor at fingertip. We measured LFCT by measuring time from re-breathing after 20 s of breath hold to the nadir of the difference of transmitted red light and infrared light, which corresponds to percutaneous oxygen saturation. Fifty patients with heart failure were enrolled. The intrasubject stability of the measurement was assessed by the intraclass correlation coefficient (ICC). The ICC calculated from 44 cases was 0.85 (95% confidence interval: 0.77–0.91), which means to have “Excellent reliability.” By measuring twice, at least one clear LFCT value was obtained in 89.1% of patients and the overall measurability was 95.7%. We conducted all LFCT measurements safely. High ICCs were obtained even after dividing patients according to age, cardiac index (CI); 0.85 and 0.84 (≥ 75 or

Longest prefix matching (LPM) is a fundamental process in IP routing used not only in traditional hardware routers but also in software middleboxes. However, the performance of LPM in software is still insufficient for processing packets at over 100 Gbps, although previous studies have tackled this issue by exploiting the CPU cache or accelerators such as GPUs. To improve the performance of software LPM further, we propose a novel LPM method called Spider, which exploits a single-instruction multiple-data (SIMD) mechanism in the CPU. Spider achieves performing LPM for up to 16 destination IP address in parallel by a routing table structure carefully designed for processing by the SIMD instructions. We evaluated Spider from the following three perspectives: the improvement of LPM performance derived from the parallelism provided by the SIMD mechanism, performance comparison with other methods, and performance scalability. The evaluation shows that Spider dramatically improves the LPM performance, which reaches 1.8-3.2 times compared with the state-of-the-art methods. Moreover, Spider achieves 5,074 million lookups per second with 16 CPU cores, which is equivalent to the processing capacity of 3.4 Tbps in short packets; the performance opens up the possibility of packet processing at the terabit-class rate by software.

Gut peristaltic movements recognized as the wave-like propagation of a local contraction are crucial for effective transportation and digestion/absorption of ingested materials. Although the physiology of gut peristalsis has been well studied in adults, it remains largely unexplored how the cellular functions underlying these coordinated tissue movements are established along the rostral-caudal gut axis during development. The chicken embryonic gut serves as an excellent experimental model for elucidating the endogenous potential and regulation of these cells since peristalsis occurs even though no ingested material is present in the moving gut. By combining video-recordings and kymography, we provide a spatial map of peristaltic movements along the entire gut posterior to the duodenum: midgut (jejunum and ileum), hindgut, caecum, and cloaca. Since the majority of waves propagate bidirectionally at least until embryonic day 12 (E12), the sites of origin of peristaltic waves (OPWs) can unambiguously be detected in the kymograph. The spatial distribution map of OPWs has revealed that OPWs become progressively confined to specific regions/zones along the gut axis during development by E12. Ablating the enteric nervous system (ENS) or blocking its activity by tetrodotoxin perturb the distribution patterns of OPWs along the gut tract. These manipulations have also resulted in a failure of transportation of inter-luminally injected ink. Finally, we have discovered a functional coupling of the endpoint of hindgut with the cloaca. When surgically separated, the cloaca ceases its acute contractions that would normally occur concomitantly with the peristaltic rhythm of the hindgut. Our findings shed light on the intrinsic regulations of gut peristalsis, including unprecedented ENS contribution and inter-region cross talk along the gut axis.

Abstract As timely measurement of the cardiac index (CI) is one of the key elements in heart failure management, a noninvasive, simple, and inexpensive method of estimating CI is keenly needed. We attempted to develop a new device that can estimate CI from the data of lung‐to‐finger circulation time (LFCT) obtained after a brief breath hold in the awake state. First, we attempted to estimate CI from the LFCT value by utilizing the correlation between 1/LFCT and CI estimated with MRI. Although we could obtain LFCT from 45 of 53 patients with cardiovascular diseases, we could not find the anticipated relation between 1/LFCT and CI. However, we realized that when we adopted only LFCT from patients with a finger temperature of ≥31°C, we could obtain a consistent and clear correlation with CI (correlation coefficient, r = .81). Thus, we next measured LFCT before and after warming the forearm. We found that LFCT decreased after the local temperature increased (from 27.5 ± 13.6 to 18.4 ± 5.3 s, p

Abstract Background Although the prognosis of core‐binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse. Methods Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22). Results Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease‐free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper‐ or hypodiploidy were included in a scoring system (named I‐CBFit). DFS rate at 2 years was 76% for patients with a low‐risk I‐CBFit score compared with 36% for those with a high‐risk I‐CBFit score (P

Sake yeast was developed exclusively in Japan. Its diversification during breeding remains largely uncharacterized. To evaluate the breeding processes of the sake lineage, we thoroughly investigated the phenotypes and differentiation of 27 sake yeast strains using high-dimensional, single-cell, morphological phenotyping. Although the genetic diversity of the sake yeast lineage is relatively low, its morphological diversity has expanded substantially compared to that of the Saccharomyces cerevisiae species as a whole. Evaluation of the different types of breeding processes showed that the generation of hybrids (crossbreeding) has more profound effects on cell morphology than the isolation of mutants (mutation breeding). Analysis of phenotypic robustness revealed that some sake yeast strains are more morphologically heterogeneous, possibly due to impairment of cellular network hubs. This study provides a new perspective for studying yeast breeding genetics and micro-organism breeding strategies.

Background: Recent studies have demonstrated that brain activities using NIRS (near-infrared spectroscopy) at baseline during cognitive tasks (e.g., N-back task) can predict the cognitive benefits of a cognitive training. In this study, we investigated whether brain activities during brain training game (BT) at baseline would predict benefits to cognitive functions after the intervention period. Methods: In a four-week double-blinded randomized control trial (RCT) 72 young adults were randomly assigned to one of the two groups: participants in the BT group played specific game, called the Brain Age. Participants in an active control group (ACT) played the puzzle game Tetris. We measured brain activity during the training games using two channel NIRS before the intervention period. Cognitive functions were tested before and after the four-week intervention period. Results: The BT showed significant improvements in inhibition, processing speed, and working memory performance compared to ACT. The left and right DLPFC (dorsolateral prefrontal cortex) brain activities during the BT at baseline were associated with improvements in inhibition and processing speed. Discussion: This randomized control trial first provides scientific evidence that DLPFC activities during BT at baseline can predict cognitive improvements after a four-week intervention period.

Body movements, such as trunk flexion and rotation, are risk factors for low back pain in occupational settings, especially in healthcare workers. Wearable motion capture systems are potentially useful to monitor lower back movement in healthcare workers to help avoid the risk factors. In this study, we propose a novel system using sheet stretch sensors and investigate the system validity for estimating lower back movement.Six volunteers (female:male = 1:1, mean age: 24.8 ± 4.0 years, height 166.7 ± 5.6 cm, weight 56.3 ± 7.6 kg) participated in test protocols that involved executing seven types of movements. The movements were three uniaxial trunk movements (i.e., trunk flexion-extension, trunk side-bending, and trunk rotation) and four multiaxial trunk movements (i.e., flexion + rotation, flexion + side-bending, side-bending + rotation, and moving around the cranial-caudal axis). Each trial lasted for approximately 30 s. Four stretch sensors were attached to each participant's lower back. The lumbar motion angles were estimated using simple linear regression analysis based on the stretch sensor outputs and compared with those obtained by the optical motion capture system.The estimated lumbar motion angles showed a good correlation with the actual angles, with correlation values of r = 0.68 (SD = 0.35), r = 0.60 (SD = 0.19), and r = 0.72 (SD = 0.18) for the flexion-extension, side bending, and rotation movements, respectively (all P < 0.05). The estimation errors in all three directions were less than 3°.The stretch sensors mounted on the back provided reasonable estimates of the lumbar motion angles. The novel motion capture system provided three directional angles without capture space limits. The wearable system possessed great potential to monitor the lower back movement in healthcare workers and helping prevent low back pain.

Among various long-term complications after conization, complete cervical stenosis is rare (