Left lobe living donor liver transplantation using the resection and partial liver segment 2-3 transplantation with delayed total hepatectomy (RAPID) procedure in cirrhotic patients: First case report in Korea.

In liver transplantation, the primary concern is to ensure an adequate future liver remnant (FLR) volume for the donor, while selecting a graft of sufficient size for the recipient. The living donor-resection and partial liver segment 2-3 transplantation with delayed total hepatectomy (LD-RAPID) procedure offers a potential solution to expand the donor pool for living donor liver transplantation (LDLT). We report the first case involving a cirrhotic patient with autoimmune hepatitis and hepatocellular carcinoma, who underwent left lobe LDLT using the LD-RAPID procedure. The living liver donor (LLD) underwent a laparoscopic left hepatectomy, including middle hepatic vein. The resection on the recipient side was an extended left hepatectomy, including the middle hepatic vein orifice and caudate lobe. At postoperative day 7, a computed tomography scan showed hypertrophy of the left graft from 320 g to 465 mL (i.e., a 45.3% increase in graft volume body weight ratio from 0.60% to 0.77%). After a 7-day interval, the diseased right lobe was removed in the second stage surgery. The LD-RAPID procedure using left lobe graft allows for the use of a small liver graft or small FLR volume in LLD in LDLT, which expands the donor pool to minimize the risk to LLD by enabling the donation of a smaller liver portion.

Prediction of very early subclinical rejection with machine learning in kidney transplantation.

Protocol biopsy is a reliable method for assessing allografts status after kidney transplantation (KT). However, due to the risk of complications, it is necessary to establish indications and selectively perform protocol biopsies by classifying the high-risk group for early subclinical rejection (SCR). Therefore, the purpose of this study is to analyze the incidence and risk factors of early SCR (within 2 weeks) and develop a prediction model using machine learning. Patients who underwent KT at Samsung Medical Center from January 2005 to December 2020 were investigated. The incidence of SCR was investigated and risk factors were analyzed. For the development of prediction model, machine learning methods (random forest, elastic net, extreme gradient boosting [XGB]) and logistic regression were used and the performance between the models was evaluated. The cohorts of 987 patients were reviewed and analyzed. The incidence of SCR was 14.6%. Borderline cellular rejection (BCR) was the most common type of rejection, accounting for 61.8% of cases. In the analysis of risk factors, recipient age (OR 0.98, p = 0.03), donor BMI (OR 1.07, p = 0.02), ABO incompatibility (OR 0.15, p < 0.001), HLA II mismatch (two [OR 6.44, p < 0.001]), and ATG induction (OR 0.41, p < 0.001) were associated with SCR in the multivariate analysis. The logistic regression prediction model (average AUC = 0.717) and the elastic net model (average AUC = 0.712) demonstrated good performance. HLA II mismatch and induction type were consistently identified as important variables in all models. The odds ratio analysis of the logistic prediction model revealed that HLA II mismatch (OR 6.77) was a risk factor for SCR, while ATG induction (OR 0.37) was a favorable factor. Early SCR was associated with HLA II mismatches and induction agent and prediction model using machine learning demonstrates the potential to predict SCR.

How job crafting behaviors influence the innovative behavior of knowledge workers in the gig economy: based on the organismic integration theory.

Introduction: The gig economy is extolled for its potential to stimulate economic and social development. This study examines the mediating roles of controlled and autonomous motivation in the relationship between job crafting and innovative behavior in the context of knowledge workers in the gig economy. Methods: To examine these relationships, we propose and test a conceptual framework using an online survey conducted among knowledge workers in China. The participants consisted of 302 knowledge workers who voluntarily participated in the study. We used structural equation modeling to test the proposed relationships among the variables. Results: Controlled and autonomous motivation mediates the relationship between job crafting and innovative behavior. Discussion: Our study shed light on the knowledge workers' motivation dilemma in the gig economy, with theoretical implications for research regarding job crafting, motivation, and practice implications about the job crafting and innovative behavior of knowledge workers.

Graft-recipient-weight ratio and lowered immunosuppression is important for the success of adult liver retransplantation.

This study analyzed the risk of liver retransplantation and factors related to better outcome. Adult liver transplantations performed during 1996-2021 were included. Comparison between first transplantation and retransplantation were performed. Among retransplantation cases, comparison between whole liver and partial liver graft was performed. Multivariable Cox analyses for analyzing risk factors for primary graft and overall patient survival were performed for the entire cohort as well as the subgroup of patients with retransplantation. A total 2237 transplantations from 2135 adults were included and 103 cases were retransplantation. A total of 44 cases (42.7%) were related to acute graft dysfunction while 59 cases (57.3%) were related to subacute or chronic graft dysfunction. Retransplantation was related poor primary graft (HR 3.439, CI 2.230-5.304, P < 0.001) and overall patient survival. (HR 2.905, CI 2.089-4.040, P < 0.001) Among retransplantations, mean serum FK506 trough level ≥ 9 ng/mL was related to poor primary graft (HR 3.692, CI 1.288-10.587, P = 0.015) and overall patient survival. (HR 2.935, CI 1.195-7.211, P = 0.019) Graft-recipient-weight ratio under 1.0% was related to poor overall patient survival in retransplantations. (HR 3.668, CI 1.150-11.698, P = 0.028). Retransplantation can be complicated with poor graft and patient survival compared to first transplantation, especially when the graft size is relatively small. Lowering the FK506 trough level during the first month can be beneficial for outcome.

Effect of pre-operative radiation therapy on surgical outcome in retroperitoneal sarcoma.

Background: A high rate of locoregional recurrence is one of the major difficulties in successful treatment of retroperitoneal sarcoma (RPS). Although pre-operative radiation therapy (RT) is considered a potential way to improve local recurrence, concerns about the associated treatment toxicity and risk of peri-operative complications need to be addressed. Hence, this study investigates the safety of pre-operative RT (preRTx) for RPS. Methods: A cohort of 198 patients with RPS who had undergone both surgery and RT was analyzed for peri-operative complications. They were divided into three groups according to the RT scheme: (1) preRTx group, (2) post-operative RT without tissue expander, and (3) post-operative RT with tissue expander. Results: The preRTx was overall well tolerated and did not affect the R2 resection rate, operative time, and severe post-operative complications. However, the preRTx group was associated with higher incidence of post-operative transfusion and admission to intensive care unit (p = 0.013 and p = 0.036, respectively), where preRTx was an independent risk factor only for the post-operative transfusion (p = 0.009) in multivariate analysis. The median radiation dose was the highest in preRTx group, although no significant difference was demonstrated in overall survival and local recurrence rate. Conclusion: This study suggests that the preRTx does not add significant post-operative morbidity to the patients with RPS. In addition, radiation dose elevation is achievable with the pre-operative RT. However, a meticulous intra-operative bleeding control is recommended in those patients, and further high-quality trials are warranted to evaluate the long-term oncological outcomes.

Improved recurrence-free survival in patients with HCC with post-transplant plasma exchange.

Total plasma exchange (TPE) can play a role in cancer treatment by eliminating immune checkpoint inhibitors. This study investigated whether TPE improved oncological outcomes in patients with HCC who underwent ABO-incompatible living donor liver transplantation (LT). The study included 152 patients who underwent ABO-incompatible living donor LT for HCC between 2010 and 2021 at Samsung Medical Center. Overall survival was analyzed using the Kaplan-Meier curve, whereas HCC-specific recurrence-free survival (RFS) was analyzed using the cumulative incidence curve after propensity score matching. Cox regression and competing risks subdistribution hazard models were used to identify the risk factors associated with overall survival and HCC-specific RFS, respectively. The propensity score matching resulted in 54 matched pairs, grouped according to whether they underwent postoperative TPE [post-transplant TPE(+)] or not [post-transplant TPE(-)]. The 5-year HCC-specific RFS cumulative incidence was superior in the post-transplant TPE (+) group [12.5% (95% CI: 3.1%-21.9%)] compared with the post-transplant TPE(-) group [38.1% (95% CI: 24.4%-51.8%), p = 0.005]. In subgroup analysis for patients with microvascular invasion and those beyond the Milan criteria, the post-transplant TPE(+) group showed significantly superior HCC-specific survival. The multivariable analysis also showed that postoperative TPE had a protective effect on HCC-specific RFS (HR = 0.26, 95% CI: 0.10-0.64, p = 0.004) and that the more post-transplant TPE was performed, the better RFS was observed (HR = 0.71, 95% CI: 0.55-0.93, p = 0.012). Post-transplant TPE was found to improve RFS after ABO-incompatible living donor LT for HCC, particularly in advanced cases with microvascular invasion and beyond Milan criteria. These findings suggest that TPE may have a potential role in improving oncological outcomes in patients with HCC undergoing LT.

Near-zero open conversion rate of laparoscopic liver resection: a high-volume single-center experience of the past 5 years.

BACKGROUND: Despite widespread adoption and technological advances in laparoscopic liver resection (LLR), conversion to laparotomy can still occur unexpectedly. Several studies have explored risk factors of open conversion (OC). However, most of these studies were conducted before 2018 and included all patients who underwent surgery at an early stage after starting LLR. The purpose of this study was to analyze the incidence and risk factors of OC in patients within the past 5 years (2017-2021). METHODS: Patients who underwent LLR at Samsung Medical Center from January 2017 to December 2021 were investigated. The incidence and causes of OC were investigated and risk factors associated with OC were also analyzed. RESULTS: A total of, 1951 patients were investigated. OC was observed in 34 patients (1.74%). The percentage of previous surgeries (50% vs. 25.5%, P < 0.001), history of hepatectomy (23.5% vs. 5.4%, P = 0.002), multi-focal disease (29.4% vs. 13.9%, P = 0.037), and posterosuperior (PS) location (64.7% vs. 39%, P = 0.004) were higher in the OC group. The most common cause of OC was adhesion (44.1%). In the analysis of risk factors associated with OC, PS location (OR 2.79, P = 0.007) and maximum tumor size (OR 0.92, P = 0.037) were statistically significant factors in multivariate analysis. CONCLUSION: The updated incidence of OC was 1.74%. The main cause of OC was adhesion. In addition, PS location and smaller tumor size were risk factors associated with OC.

An Examination of the Effects of Job Insecurity on Counterproductive Work Behavior Through Organizational Cynicism: Moderating Roles of Perceived Organizational Support and Quality of Leader-Member Exchange.

Job insecurity can trigger cynical attitudes and ultimately lead to harmful behaviors in organizations under the current fast-changing business environment. Drawing on psychological contract theory, this study aimed to investigate the relationship between job insecurity and counterproductive work behavior (CWB) by focusing on the mediating role of organizational cynicism and moderating roles of perceived organizational support (POS) and leader-member exchange (LMX). The data used for the analysis came from a survey that targeted tourism-related industries in South Korea, and 296 responses were finally analyzed. We analyzed reliability, correlation, and mediation, and conducted confirmatory factor analysis, regression analysis, and moderation analysis using SPSS PROCESS macro v. 3.5, with AMOS v. 25.0. The key findings of this study are as follows. First, we found that job insecurity was positively related to CWB. Second, organizational cynicism mediated the relationship between job insecurity and CWB. Third, POS and LMX intensified the negative effects of job insecurity and organizational cynicism, affecting CWB. These results imply that employees with a high level of POS and LMX are likely to have opportunistic behaviors (e.g., abuse, absences, sabotage) by abusing the support and trust from their organizations. The implications for research and practice, limitations, and directions for future research are discussed.

The Role of Preoperative 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Retroperitoneal Sarcoma.

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was used to predict pathologic grades based on the maximum standardized uptake value (SUVmax) in soft tissue sarcoma and bone sarcoma. In retroperitoneal sarcoma (RPS), the effectiveness of PET was not well known. This study was designed to investigate the association of SUVmax with histopathologic grade and evaluate the usefulness of 18F-FDG PET/CT before operation. Patients at Samsung Medical Center undergoing primary surgery for retroperitoneal sarcoma with preoperative 18F-FDG PET/CT imaging between January 2001 and February 2020 were investigated. The relationship between SUVmax and histologic features was assessed. The association of SUVmax with overall survival (OS), local recurrence (LR), and distant metastasis (DM) were studied. Of the total 129 patients, the most common histologic subtypes were liposarcoma (LPS; 68.2%) and leiomyosarcoma (LMS; 15.5%). The median SUVmax was 4.5 (range, 1- 29). Moreover, SUVmax was correlated with tumor grade (p < 0.001, Spearman coefficient; 0.627) and mitosis (p < 0.001, Spearman coefficient; 0.564) and showed a higher value in LMS (12.04 ± 6.73) than in dedifferentiated liposarcoma (DDLPS; 6.32 ± 4.97, p = 0.0054). SUVmax was correlated with pathologic parameters (tumor grade and mitosis) in RPS and was higher in the LMS group than the DDLPS group. The optimal SUVmax threshold to distinguish high tumor grade was 4.8. Those with a SUVmax greater than the threshold showed poor prognosis regarding OS, LR, and DM (p < 0.001).

Analysis of the Effect of Tumor-Grade Change on the Prognosis of Retroperitoneal Sarcoma.

In retroperitoneal sarcoma (RPS), the change in the tumor grade from the primary tumor to the first local recurrence, and the effect of this change on prognosis, are unknown. The aim of this study is to analyze whether these changes affect the prognosis of RPS. Patients who underwent surgery for a first locally recurrent RPS at Samsung Medical Center from January 2001 to February 2020 were included. The pathologic features of primary and recurrent tumors were compared, and the outcomes were measured. A total of 49 patients were investigated. There were 25 patients with different grades of primary and recurrent tumors. The improving, stable, and worsening groups contained 16 (32.7%), 24 (49%), and 9 (18.3%) patients, respectively. There was no significant difference in the prognosis between the three groups. In the analyses of the factors that affect the OS, a high grade of the primary tumor (p = 0.023) and the size of the recurrent tumor (p = 0.032) were statistically significant in both univariate and multivariate analyses. In a factor analysis of the second LR, a high-grade recurrent tumor (p = 0.032) was the only significant factor. There were tumor-grade changes between the primary tumor and recurrent tumor in RPS. However, the most important factor in prognosis is a high grade of the primary tumor.

Indications for open hepatectomy in the era of laparoscopic liver resection: a high volume single institutional study.

Background/Aim: Since the introduction of laparoscopy for liver resection in the 1990s, the performance of laparoscopic liver resection (LLR) has been steadily increasing. However, there is currently no data on the extent to which laparoscopy is used for liver resection. Herein, we investigated the extent to which laparoscopy is performed in liver resection and sought to determine whether surgeons prefer laparoscopy or laparotomy in the posterosuperior (PS) segment. Methods: For this retrospective observational study, we enrolled patients who had undergone liver resection at the Samsung Medical Center between January 2020 and December 2021. The proportion of LLR in liver resection was calculated, and the incidence and causes of open conversion were investigated. Results: A total of 1,095 patients were included in this study. LLR accounted for 79% of the total liver resections. The percentage of previous hepatectomy (16.2% vs. 5.9%, P<0.001) and maximum tumor size (median 4.8 vs. 2.8, P<0.001) were higher in the open liver resection (OLR) group. Subgroup analysis revealed that tumor size (median 6.3 vs. 2.9, P<0.001) and surgical extent (P<0.001) in the OLR group were larger than those in the LLR group. The most common cause of open conversion (OC) was adhesion (57%), and all OC patients had tumors in the PS. Conclusions: We investigated the recent preference of practical surgeons in liver resection, and found that surgeons preferred OLR to LLR when treating a large tumor located in the PS.

Postoperative Outcomes of Distal Pancreatectomy for Retroperitoneal Sarcoma Abutting the Pancreas in the Left Upper Quadrant.

BACKGROUND: En bloc resection of the tumor with adjacent organs is recommended for localized retroperitoneal sarcoma (RPS). However, resection of the pancreas is controversial because it may cause serious complications, such as pancreatic fistula or bleeding. Thus, we evaluated the outcomes of distal pancreatectomy (DP) in pancreas-abutting RPS of the left upper quadrant (LUQ). METHODS: We retrospectively reviewed all consecutive patients who underwent surgery for RPS between September 2001 and April 2020. We selected 150 patients with all or part of their tumor located in the LUQ on preoperative computed tomography. Eighty-six patients who had tumors abutting the pancreas were finally enrolled in our study. RESULTS: Fifty-three patients (53/86; 61.6%) were included in the non-DP group, and 33 patients (33/86; 38.4%) were included in the DP group. Total postoperative complications and complication rates for those Clavien-Dindo grade 3 or higher were similar between the non-DP group and DP group (p = 0.290 and p = 0.550). In the DP group, grade B pancreatic fistulae occurred in 18.2% (6/33) of patients, but grade C pancreatic fistulae were absent, and microscopic pancreatic invasion was noted in 42.4% (14/33) of patients. During multivariate analysis, microscopic pancreatic invasion was deemed a risk factor for local recurrence (p = 0.029). However, there were no significant differences on preoperative computed tomography findings between the pancreatic invasion and non-invasion groups. CONCLUSION: DP is a reasonable procedure for pancreas-abutting RPS located at the LUQ when both complications and complete resection are considered.

Maximum standardized uptake value on 18F-fluorodeoxyglucose positron emission tomography/computed tomography improves outcome prediction in retroperitoneal liposarcoma.

While 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been investigated in extremity sarcomas, there is no evidence on its usefulness in retroperitoneal sarcoma. This study was designed to evaluate the usefulness of 18F-FDG PET/CT in predicting aggressiveness of retroperitoneal liposarcoma. Patients experienced surgery for retroperitoneal liposarcoma from November 2007 to February 2018 and underwent preoperative 18F-FDG PET/CT were included. Preoperative maximum standardized uptake value (SUVmax) was calculated. To evaluate the predictability of SUVmax for Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 3, receiver operating characteristics (ROC) curve analysis was performed. To analyze whether SUVmax can be a risk factor for prognosis, multivariable Cox regression was performed including potential risk factors regarding operation and histopathology. A total of 133 patients were included. ROC curve showed area under the curve of 0.877 (P < 0.001), with a cut-off point of 4.5 SUVmax showing 85.7% sensitivity and 78.3% specificity. Cox analyses showed that SUVmax > 4.5 was a significant factor for recurrence-free survival (HR = 2.148, CI 1.301-3.546, P = 0.003) and overall survival (HR = 5.052, CI 1.854-13.766, P = 0.002). SUVmax is highly predictive of FNCLCC grade 3 and SUVmax > 4.5 can be used as a prognostic factor before obtaining the histopathology.

Capsanthin Inhibits both Adipogenesis in 3T3-L1 Preadipocytes and Weight Gain in High-Fat Diet-Induced Obese Mice.

Adipogenesis in murine preadipocyte 3T3L-1 has been used as a model system to study anti-obese bioactive molecules. During adipogenesis in 3T3-L1 preadipocytes, we found that capsanthin inhibited adipogenesis (IC50; 2.5 µM) and also showed lipolytic activity in differentiated adipocytes from the preadipocytes (ED50; 872 nM). We identified that the pharmacological activity of capsanthin on adipogenesis in 3T3-L1 was mainly due to its adrenoceptor-ß2-agonistic activity. In high-fat diet animal model study, capsanthin significantly enhanced spontaneous locomotive activities together with progressive weight-loss. The capsanthin-induced activation of kinetic behavior in mice was associated with the excessive production of ATP initiated by both the enhanced lipolytic activity together with accelerated oxidation of fatty acids due to the adrenoceptor ß2-agonistic activity of capsanthin. Capsanthin also dose-dependently increased adiponectin and p-AMPK activity in high fat diet animals, suggesting that capsanthin has both anti-obesity and insulin sensitizing activities.

Enhancing the Physical Properties and Lifespan of Bacterial Quorum Quenching Media through Combination of Ionic Cross-Linking and Dehydration.

Quorum quenching (QQ) bacteria entrapped in a polymeric composite hydrogel (QQ medium) have been successfully applied in membrane bioreactors (MBRs) for effective biofouling control. However, in order to bring QQ technology closer to practice, the physical strength and lifetime of QQ media should be improved. In this study, enforcement of physical strength, as well as an extension of the lifetime of a previously reported QQ bacteria entrapping hollow cylinder (QQ-HC), was sought by adding a dehydration procedure following the cross-linking of the polymeric hydrogel by inorganic compounds like Ca2+ and boric acid. Such prepared medium demonstrated enhanced physical strength possibly through an increased degree of physical cross-linking. As a result, a longer lifetime of QQ-HCs was confirmed, which led to improved biofouling mitigation performance of QQ-HC in an MBR. Furthermore, QQ-HCs stored under dehydrated condition showed higher QQ activity when the storage time lasted more than 90 days owing to enhanced cell viability. In addition, the dormant QQ activity after the dehydration step could be easily restored through reactivation with real wastewater, and the reduced weight of the dehydrated media is expected to make handling and transportation of QQ media highly convenient and economical in practice.

Effects of Quorum Quenching on the Microbial Community of Biofilm in an Anoxic/Oxic MBR for Wastewater Treatment.

Recently, bacterial quorum quenching (QQ) has been proven to have potential as an innovative approach for biofouling control in membrane bioreactors (MBRs) for advanced wastewater treatment. Although information regarding the microbial community is crucial for the development of QQ strategies, little information exists on the microbial ecology in QQ-MBRs. In this study, the microbial communities of biofilm were investigated in relation to the effect of QQ on anoxic/oxic MBRs. Two laboratory-scale MBRs were operated with and without QQ-beads (QQ-bacteria entrapped in beads). The transmembrane pressure increase in the QQ-MBRs was delayed by approximately 100-110% compared with conventional- and vacant-MBRs (beads without QQ-bacteria) at 45 kPa. In terms of the microbial community, QQ gradually favored the development of a diverse and even community. QQ had an effect on both the bacterial composition and change rate of the bacterial composition. Proteobacteria and Bacteroidetes were the most dominant phyla in the biofilm, and the average relative composition of Proteobacteria was low in the QQ-MBR. Thiothrix sp. was the dominant bacterium in the biofilm. The relative composition of Thiothrix sp. was low in the QQ-MBR. These findings provide useful information that can inform the development of a new QQ strategy.

Comparison of microbial communities of activated sludge and membrane biofilm in 10 full-scale membrane bioreactors.

Operation of membrane bioreactors (MBRs) for wastewater treatment is hampered by the membrane biofouling resulting from microbial activities. However, the knowledge of the microbial ecology of both biofilm and activated sludge in MBRs has not been sufficient. In this study, we scrutinized microbial communities of biofilm and activated sludge from 10 full-scale MBR plants. Overall, Flavobacterium, Dechloromonas and Nitrospira were abundant in order of abundance in biofilm, whereas Dechloromonas, Flavobacterium and Haliscomenobacter in activated sludge. Community structure was analyzed in either biofilm or activated sludge. Among MBRs, as expected, not only diversity of microbial community but also its composition was different from one another (p < 0.05). Between the biofilm and activated sludge, community composition made significant difference, but its diversity measures (i.e., alpha diversity, e.g., richness, diversity and evenness) did not (p > 0.05). Effects of ten environmental factors on community change were investigated using Spearman correlation. MLSS, HRT, F/M ratio and SADm explained the variation of microbial composition in the biofilm, whereas only MLSS did in the activated sludge. Microbial networks were constructed with the 10 environmental factors. The network results revealed that there were different topological characteristics between the biofilm and activated sludge networks, in which each of the 4 factors had different associations with microbial nodes. These results indicated that the different microbial associations were responsible for the variation of community composition between the biofilm and activated sludge.

Crossing the Border between Laboratory and Field: Bacterial Quorum Quenching for Anti-Biofouling Strategy in an MBR.

Quorum quenching (QQ) has recently been acknowledged to be a sustainable antifouling strategy and has been investigated widely using lab-scale membrane bioreactor (MBR) systems. This study attempted to bring this QQ-MBR closer to potential practical application. Two types of pilot-scale QQ-MBRs with QQ bacteria entrapping beads (QQ-beads) were installed and run at a wastewater treatment plant, feeding real municipal wastewater to test the systems' effectiveness for membrane fouling control and thus the amount of energy savings, even under harsh environmental conditions. The rate of transmembrane pressure (TMP) build-up was significantly mitigated in QQ-MBR compared to that in a conventional-MBR. Consequently, QQ-MBR can substantially reduce energy consumption by reducing coarse bubble aeration without compromising the effluent water quality. The addition of QQ-beads to a conventional MBR substantially affected the EPS concentrations, as well as microbial floc size in the mixed liquor. Furthermore, the QQ activity and mechanical stability of QQ-beads were well maintained for at least four months, indicating QQ-MBR has good potential for practical applications.