Four weeks of off-treatment follow-up is sufficient to determine virologic responses at off-treatment week 12 in patients with hepatitis C virus infection receiving fixed-dose pangenotypic direct-acting antivirals.

Early confirmation of sustained virologic response (SVR) or viral relapse after direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection is essential based on public health perspectives, particularly for patients with high risk of nonadherence to posttreatment follow-ups. A total of 1011 patients who achieved end-of-treatment virologic response, including 526 receiving fixed-dose pangenotypic DAAs, and 485 receiving other types of DAAs, who had available off-treatment weeks 4 and 12 serum HCV RNA data to confirm SVR at off-treatment week 12 (SVR12) or viral relapse were included. The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 to predict patients with SVR12 or viral relapse were reported. Furthermore, we analyzed the proportion of concordance between SVR12 and SVR24 in 943 patients with available SVR24 data. The PPV and NPV of SVR4 to predict SVR12 were 98.5% (95% confidence interval [CI]: 98.0-98.9) and 100% (95% CI: 66.4-100) in the entire population. The PPV of SVR4 to predict SVR12 in patients receiving fixed-dose pangenotypic DAAs was higher than those receiving other types of DAAs (99.8% [95% CI: 98.9-100] vs. 97.1% [95% CI: 96.2-97.8], p < 0.001). The NPVs of SVR4 to predict viral relapse were 100%, regardless of the type of DAAs. Moreover, the concordance between SVR12 and SVR24 was 100%. In conclusion, an off-treatment week 4 serum HCV RNA testing is sufficient to provide an excellent prediction power of SVR or viral relapse at off-treatment week 12 among patients with HCV who are treated with fixed-dose pangenotypic DAAs.

Feasibility of new-generation endocytoscopy for the real-time diagnosis of ampullary lesions: A pilot study (with video).

BACKGROUND AND AIM: An early and accurate diagnosis of ampullary neoplasia is crucial; however, sampling bias is still a major concern. New-generation endocytoscopy enables real-time visualization of cellular structures and enables an accurate pathological prediction; however, its feasibility for small ampullary lesions has never been investigated. METHODS: We developed a novel endocytoscopic (EC) classification system for ampullary lesions after an expert review and agreement from five experienced endoscopists and one pathologist. We then consecutively enrolled a total of 43 patients with an enlarged ampulla (< 3 cm), all of whom received an endocytoscopic examination. The feasibility of endocytoscopy was evaluated, and the performance of the EC classification system was then correlated with the final histopathology. RESULTS: In five cases (11.6%), the endocytoscope could not approach the ampulla, and these cases were defined as technical failure. Among the remaining 38 patients, 8 had histopathology-confirmed adenocarcinoma, 15 had adenoma, and 15 had non-neoplastic lesions. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the EC classification system to diagnose ampullary neoplasias were 95.7%, 86.7%, 91.7%, 92.9%, and 92.1%, respectively. Moreover, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the EC classification to diagnose ampullary cancer were 62.5%, 100%, 100%, 90.9%, and 92.1%, respectively. One case with intra-ampullary papillary-tubular carcinoma was classified as having a non-neoplastic lesion by endocytoscopy. CONCLUSIONS: Endocytoscopy and the novel EC classification system demonstrated good feasibility to discriminate ampullary neoplasias from non-neoplastic lesions and may be useful for optical biopsies of clinically suspicious ampullary lesions.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Application of the IOC Relative Energy Deficiency in Sport (REDs) Clinical Assessment Tool version 2 (CAT2) across 200+ elite athletes.

OBJECTIVE: This cross-sectional retrospective and prospective study implemented the 2023 International Olympic Committee Relative Energy Deficiency in Sport (REDs) Clinical Assessment Tool version 2 (CAT2) to determine the current severity of REDs (primary outcome) and future risk of bone stress injuries (BSI, exploratory outcome) in elite athletes. METHODS: Female (n=143; 23.3±4.3 years) and male (n=70; 23.1±3.7 years) athletes (performance tier 3 (52%), tier 4 (36%), tier 5 (12%)) participated in a baseline CAT2 (with minor modifications) assessment, including a self-report questionnaire (menstrual function (females), BSI, Eating Disorder Examination Questionnaire (EDE-Q)), bone mineral density (BMD via DXA) and fasted blood analysis (triiodothyronine (T3), testosterone, cholesterol). Athletes were assigned a green, yellow, orange or red light via CAT2. The prospective risk of new self-report of physician-diagnosed BSI was assessed over a subsequent 6-24 months. RESULTS: REDs prevalence was 55% green, 36% yellow, 5% orange and 4% red light. The CAT2 identified a greater prevalence of amenorrhoea and BSI and lower T3, testosterone and BMD (p<0.01) in red, orange and yellow (those with REDs) versus green light. ORs for a prospective self-reported BSI (majority physician diagnosed) were greater in orange vs green (OR 7.71, 95% CI (1.26 to 39.83)), in females with severe amenorrhoea (OR 4.6 (95% CI 0.98 to 17.85)), in males with low sex drive (OR 16.0 (95% CI 4.79 to 1038.87)), and athletes with elevated EDE-Q global scores (OR 1.45 (95% CI 0.97 to 1.97)). CONCLUSION: The CAT2 has high validity in demonstrating current severity of REDs, with increased future risk of self-reported BSI in athletes with a more severe REDs traffic light category.

Gallic acid attenuates metastatic potential of human colorectal cancer cells through the miR-1247-3p-modulated integrin/FAK axis.

Colorectal cancer (CRC) exhibits highly metastatic potential even in the early stages of tumor progression. Gallic acid (GA), a common phenolic compound in plants, is known to possess potent antioxidant and anticancer activities, thereby inducing cell death or cell cycle arrest. However, whether GA reduces the invasiveness of CRC cells without inducing cell death remains unclear. Herein, we aimed to investigate the antimetastatic activity of low-dose GA on CRC cells and determine its underlying mechanism. Cell viability and tumorigenicity were analyzed by MTS, cell adhesion, and colony formation assay. Invasiveness was demonstrated using migration and invasion assays. Changes in protein phosphorylation and expression were assessed by Western blot. The involvement of microRNAs was validated by microarray analysis and anti-miR antagonist. Our findings showed that lower dose of GA (≤100 µM) did not affect cell viability but reduced the capabilities of colony formation, cell adhesion, and invasiveness in CRC cells. Cellularly, GA downregulated the cellular level of integrin αV/ß3, talin-1, and tensin and diminished the phosphorylated FAK, paxillin, Src, and AKT in DLD-1 cells. Microarray results revealed that GA increased miR-1247-3p expression, and pretreatment of anti-miR antagonist against miR-1247-3p restored the GA-reduced integrin αV/ß3 and the GA-inhibited paxillin activation in DLD-1 cells. Consistently, the in vivo xenograft model showed that GA administration inhibited tumor growth and liver metastasis derived from DLD-1 cells. Collectively, our findings indicated that GA inhibited the metastatic capabilities of CRC cells, which may result from the suppression of integrin/FAK axis mediated by miR1247-3p.

Clinical outcomes of different types of metallic stents in malignant distal duodenum stenosis: A retrospective study.

BACKGROUND/PURPOSE: Endoscopic stenting at malignant distal duodenum stenosis (MDDS) is challenging because of the duodenal C-loop configuration, the acute angle of the duodenojejunal junction, and the limited length of the endoscope. Few studies have investigated the clinical outcomes of stenting at the distal duodenum. Therefore, this study aimed to investigate the clinical outcomes of treating MDDS with different types of metallic stents. METHODS: From January 2012 to December 2020, fifty-six patients with MDDS who underwent duodenal stenting were enrolled for analysis. Thirty-five patients received uncovered self-expandable metallic stents (UC-SEMS), and twenty-one patients received partially covered self-expandable metallic stents (PC-SEMS). All patients were followed up till death or for 18 months. The clinical success rate, stent dysfunction rate, and stent patency were compared between the groups. Multivariate analysis was conducted to identify factors related to stent dysfunction. RESULTS: The clinical success rates were 85.7 % in both the UC-SEMS and PC-SEMS groups. Stent dysfunction rates (UC-SEMS: 34.3 %, PC-SEMS: 38.1 %, p = 0.773) and the average stent patency (UC-SEMS: 117.2 days, PC-SEMS: 100.0 days, p = 0.576) were not statistically different between the groups. Multivariate analysis disclosed the age ≥65 years was significantly related to stent dysfunction (odds ratio: 4.78, p = 0.031). CONCLUSION: Both UC-SEMS and PC-SEMS are safe and effective treatment options for MDDS. However, stent dysfunction remains a significant issue to overcome, particularly in the elderly. Further research is needed to explore novel strategies that can improve the effectiveness of stent placement and reduce the risk of stent dysfunction.

Predicting Athlete Workload in Women's Rugby Sevens Using GNSS Sensor Data, Contact Count and Mass.

The use of session rating of perceived exertion (sRPE) as a measure of workload is a popular athlete load monitoring tool. However, the nature of sRPE means the contribution of salient, sport-specific factors to athlete load in field sports is challenging to isolate and quantify. In rugby sevens, drivers of load include high-speed running and physical contact. In soccer and men's rugby, union acceleration/deceleration also influences load. These metrics are evaluated using data from global navigation satellite system (GNSS) sensors worn by athletes. Research suggests that sensor data methods for identifying load in men's rugby do not accurately quantify female athlete loads. This investigation examined how mass, contact, and accelerations and decelerations at different speeds contribute to load in women's rugby sevens. The study evaluated 99 international matches, using data from 19 full-time athletes. GNSS measures, RPE, athlete mass, and contact count were evaluated using a linear mixed-model regression. The model demonstrated significant effects for low decelerations at low and high speeds, mass, distance, and contact count explaining 48.7% of the global variance of sRPE. The use of acceleration/deceleration and speed from GNSS sensors alongside mass, as well as contact count, presents a novel approach to quantifying load.

The Determination of On-Water Rowing Stroke Kinematics Using an Undecimated Wavelet Transform of a Rowing Hull-Mounted Accelerometer Signal.

Boat acceleration profiles can provide valuable information for coaches and practitioners to make meaningful technical interventions and monitor the determinants of success in rowing. Previous studies have used simple feature detection methods to identify key phases within individual strokes, such as drive onset, drive time, drive offset and stroke time. However, based on skill level, technique or boat class, the hull acceleration profile can differ, making robust feature detection more challenging. The current study's purpose is to employ the undecimated wavelet transform (UWT) technique to detect individual features in the stroke acceleration profile from a single rowing hull-mounted accelerometer. In this investigation, the temporal and kinematic values obtained using the AdMosTM sensor in conjunction with the UWT processing approach were strongly correlated with the comparative measures of the Peach™ instrumented oarlock system. The measures for stroke time displayed very strong agreeability between the systems for all boat classes, with ICC values of 0.993, 0.963 and 0.954 for the W8+, W4- and W1x boats, respectively. Similarly, the drive time was also very consistent, with strong to very strong agreeability, producing ICC values of 0.937, 0.901 and 0.881 for the W8+, W4- and W1x boat classes. Further, a Bland-Altman analysis displayed little to no bias between the AdMosTM-derived and Peach™ measures, indicating that there were no systematic discrepancies between signals. This single-sensor solution could form the basis for a simple, cost-effective and accessible alternative to multi-sensor instrumented systems for the determination of sub-stroke kinematic phases.

The Therapeutic Role of NPS-1034 in Pancreatic Ductal Adenocarcinoma as Monotherapy and in Combination with Chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.

Predicting Sprint Performance From the Vertical and Horizontal Jumps in National Football League Combine Athletes.

ABSTRACT: Agar-Newman, DJ, MacRae, F, Tsai, M-C, and Klimstra, M. Predicting sprint performance from the vertical and horizontal jumps in National Football League Combine athletes. J Strength Cond Res 38(8): 1433-1439, 2024-Identifying fast athletes is an important part of the National Football League (NFL) Combine. However, not all athletes partake in the 36.58-m sprint, and relying on this single test may miss potentially fast athletes. Therefore, the purpose of this study was to determine whether sprinting times can be predicted using simple anthropometric and jumping measures. Data from the NFL Combine between the years 1999-2020 inclusive were used (n = 4,149). Subjects had a mean (±SD) height = 1.87 ± 0.07 m and body mass = 111.96 ± 20.78 kg. The cross-validation technique was used, partitioning the data into a training set (n = 2,071) to develop regression models to predict time over the 9.14-, 9.14- to 18.29-, 18.29- to 36.58-m, and 36.58-m segments using vertical jump, broad jump, height, and mass as the independent variables. The models were then evaluated against a test set (n = 2,070) for agreement. Statistically significant (p < 0.01) models were determined for 9.14-m time (adjusted R2 = 0.76, SEE = 0.05 seconds), 9.14- to 18.29-m time (adjusted R2 = 0.74, SEE = 0.04 seconds), 18.29- to 36.59-m time (adjusted R2 = 0.79, SEE = 0.07 seconds), and 36.58-m time (adjusted R2 = 0.84, SEE = 0.12 seconds). When evaluated against the test set, the models showed biases of -0.05, -0.04, -0.02, and -0.02 seconds and root-mean-square error of 0.07, 0.05, 0.07, and 0.12 seconds for the 9.14-, 9.14- to 18.29-, 18.29- to 36.58-m, and 36.58-m segments, respectively. However, 5-6% of the predictions lay outside of the limits of agreement. This study provides 4 formulae that can be used to predict sprint performance when the 36.58-m sprint test is not performed, and practitioners can use these equations to determine training areas of opportunity when working with athletes preparing for the NFL Combine.

Randomized trial of contrast-enhanced harmonic guidance versus fanning technique for EUS-guided fine-needle biopsy sampling of solid pancreatic lesions.

BACKGROUND AND AIMS: For EUS-guided fine-needle biopsy sampling (EUS-FNB) of solid pancreatic lesions (SPLs), the role of sampling strategy between targeted biopsy sampling and wide sampling has not been reported. This study aimed to investigate the benefits of the 2 sampling techniques on EUS-FNB using rapid on-site evaluation. METHODS: Patients with SPLs were prospectively enrolled and randomly assigned (1:1) to undergo EUS-FNB using either contrast guidance or the fanning technique. The primary outcome was the total number of passes required to establish a diagnosis, and secondary outcomes were overall diagnostic accuracy and adverse event rates. RESULTS: One hundred eighteen patients were enrolled from February 2019 to January 2021, with 59 patients assigned to each group. There was no significant difference in the total number of passes required to establish a diagnosis between the contrast and fanning groups (median, 1 [interquartile range, 1-1] vs 1 [interquartile range, 1-2], respectively; P = .629). The sensitivity, specificity, and diagnostic accuracy in the contrast group was 100%, 66.7%, and 98.3% and in the fanning group 100%, 100%, and 100%, respectively (P = 1). An SPL <4 cm (odds ratio, 2.47; 95% confidence interval, 1.05-5.81; P = .037) and macroscopic visible core length >1 cm (odds ratio, 2.89; 95% confidence interval, 1.07-7.84; P = .037) were independently associated with increased cytologic and histologic accuracy. CONCLUSIONS: The diagnostic accuracy of EUS-FNB with the fanning technique for SPLs was comparable with the contrast guidance technique. Without additional cost, EUS-FNB with the fanning technique may be preferred for SPLs. (Clinical trial registration number: NCT04924725.).

A Simple and Valid Method to Calculate Wheelchair Frame Rotation Using One Wheel-Mounted IMU.

Wheelchair sports have been using Inertial Measurement Units (IMU) to measure mobility metrics during training, testing and competition. Presently, the most suitable solution to calculate wheelchair speed and frame rotation is the 3IMU method as there is uncertainty about the ability of a one wheel-mounted IMU (1IMU) approach to calculate wheelchair frame rotational kinematics. A new method for calculating wheelchair frame rotational kinematics using a single wheel-mounted IMU is presented and compared to a criterion measurement using a wheelchair-frame-mounted IMU. Goodness-of-fit statistics demonstrate very strong linear relationships between wheelchair frame angular velocity calculated from the wheel-mounted IMUs and a wheelchair-frame-mounted IMU. Root mean square error (RMSE), mean absolute error (MAE) and Bland-Altman analysis show very small differences between the wheelchair frame angular velocity calculated from the wheel-mounted IMUs and the wheelchair-frame-mounted IMU. This study has demonstrated a simple and accurate approach to estimating wheelchair frame rotation using one wheel-mounted IMU during an elite wheelchair athlete agility task. Future research is needed to reexamine and compare wheelchair mobility metrics determined using the 3IMU and 1IMU solutions using this new approach.

Wheelchair Rugby Sprint Force-Velocity Modeling Using Inertial Measurement Units and Sport Specific Parameters: A Proof of Concept.

BACKGROUND: Para-sports such as wheelchair rugby have seen increased use of inertial measurement units (IMU) to measure wheelchair mobility. The accessibility and accuracy of IMUs have enabled the quantification of many wheelchair metrics and the ability to further advance analyses such as force-velocity (FV) profiling. However, the FV modeling approach has not been refined to include wheelchair specific parameters. PURPOSE: The purpose of this study was to compare wheelchair rugby sprint FV profiles, developed from a wheel-mounted IMU, using current mono-exponential modeling techniques against a dynamic resistive force model with wheelchair specific resistance coefficients. METHODS: Eighteen athletes from a national wheelchair rugby program performed 2 × 45 m all-out sprints on an indoor hardwood court surface. RESULTS: Velocity modelling displayed high agreeability, with an average RMSE of 0.235 ± 0.07 m/s-1 and r2 of 0.946 ± 0.02. Further, the wheelchair specific resistive force model resulted in greater force and power outcomes, better aligning with previously collected measures. CONCLUSIONS: The present study highlights the proof of concept that a wheel-mounted IMU combined with wheelchair-specific FV modelling provided estimates of force and power that better account for the resistive forces encountered by wheelchair rugby athletes.

The Influence of Physical Contact on Athlete Load in International Female Rugby Sevens.

ABSTRACT: Epp-Stobbe, A, Tsai, M-C, Morris, C, and Klimstra, M. The influence of physical contact on athlete load in international female rugby sevens. J Strength Cond Res 37(2): 383-387, 2023-Although self-reported rate of perceived exertion (RPE) is a simple and popular metric for monitoring player loads, this holistic measure may not adequately represent the distinct contributing factors to athlete loading in team sports, such as contact load. The purpose of this investigation is to determine the relationship between the number of contacts experienced and playing time on RPE in elite women's rugby sevens athletes during competition. Additionally, we examine the contribution of the number of contacts and playing time to RPE. The data collected included RPE, playing time, and number of contacts from 1 team participating in 74 international women's sevens matches. The relationship was modeled using multiple linear regression. Results, including the coefficients for the number of contacts and playing time, were significant (p < 0.001), and R2adjusted was 0.3063. Because contacts are accounted for within the measure of RPE in the proposed model, this further supports the value of RPE as a global measure of athlete experience. However, this study has found a different relationship between RPE and playing time dependent on the number of contacts, such that the influence of playing time on RPE decreases as the number of contacts increase. Ultimately, this may mean that the weighting of individual salient factors affecting player loads, such as the number of contacts or playing time, depend on the levels of all known and potentially unknown factors experienced and may limit the use of RPE when contextualizing player load across athletes. Taken together, the findings suggest that the number of contacts, playing time, and RPE should be considered when monitoring athlete loads while further substantiating the need for more, and higher resolution, measures to better quantify competition loads in contact team sports.

Concurrent Validity and Reliability of Different Technologies for Sprint-Derived Horizontal Force-Velocity-Power Profiling.

ABSTRACT: Cormier, P, Tsai, M-C, Meylan, C, Agar-Newman, D, Epp-Stobbe, A, Kalthoff, Z, and Klimstra, M. Concurrent validity and reliability of different technologies for sprint-derived horizontal force-velocity-power profiling. J Strength Cond Res 37(6): 1298-1305, 2023-This study evaluated the validity and reliability of common systems to assess sprint-derived horizontal force-velocity-power ( FVPH ) profile metrics. Two double constellation athlete monitoring systems (STATSports Apex, Catapult Vector S7) and one timing gate system were compared with a radar gun for the computation of FVPH metrics. Intersystem validity was assessed using intraclass correlation coefficients (ICC), Pearson's correlation coefficients ( R2 ), and Bland-Altman plots with absolute and percent agreement. Intrasystem reliability was assessed with agreement bias and ICC. STATSports demonstrated moderate agreement for F0 , Pmax , τ, and Drf (8.62, 6.46, -9.81, and 9.96%, respectively) and good agreement for V0 and MSS (-2.18 and -1.62%). Catapult displayed good agreement across all metrics ( F0 , V0 , Pmax , MSS, τ, and Drf : -0.96, -0.89, -1.85, -0.84, 0.38, and -0.27%, respectively). Timing gates demonstrated good agreement with V0 and MSS (-2.62 and -1.71%) and poor agreement with F0 , Pmax , τ, and Drf (19.17, 16.64, -20.49, and 20.18%, respectively). Intrasystem reliability demonstrated good agreement (<2% bias) with very large to near-perfect ICC (0.84-0.99) for Catapult and STATSports systems. Overall, GPS/GNSS 10 Hz technology is reliable across devices and can provide moderate-to-good accuracy of FVPH metrics in single maximal effort sprints. However, Catapult provided better agreement for more FVPH metrics than STATSports, which may be related to differences in proprietary algorithms. Also, modeling timing gate data using current FVPH profiling techniques results in poor bias that requires greater investigation. GPS/GNSS data can be used for FVPH profiling, which could inform performance and rehabilitation processes.

PNU-74654 Induces Cell Cycle Arrest and Inhibits EMT Progression in Pancreatic Cancer.

Background and Objectives: PNU-74654, a Wnt/ß-catenin pathway inhibitor, has an antiproliferative effect on many cancer types; however, its therapeutic role in pancreatic cancer (PC) has not yet been demonstrated. Here, the effects of PNU-74654 on proliferation and cell cycle phase distribution were studied in PC cell lines. Materials and Methods: The cancer-related molecular pathways regulated by PNU-74654 were determined by a proteome profiling oncology array and confirmed by western blotting. Results: The cell viability and proliferative ability of PC cells were decreased by PNU-74654 treatment. G1 arrest was observed, as indicated by the downregulation of cyclin E and cyclin-dependent kinase 2 (CDK2) and the upregulation of p27. PNU-74654 inhibited the epithelial-mesenchymal transition (EMT), as determined by an increase in E-cadherin and decreases in N-cadherin, ZEB1, and hypoxia-inducible factor-1 alpha (HIF-1α). PNU-74654 also suppressed cytoplasmic and nuclear ß-catenin and impaired the NF-κB pathway. Conclusions: These results demonstrate that PNU-74654 modulates G1/S regulatory proteins and inhibits the EMT, thereby suppressing PC cell proliferation, migration, and invasion. The synergistic effect of PNU-74654 and chemotherapy or the exclusive use of PNU-74654 may be therapeutic options for PC and require further investigation.

Sofosbuvir/velpatasvir with or without low-dose ribavirin for patients with chronic hepatitis C virus infection and severe renal impairment.

OBJECTIVE: Data regarding the real-world effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) with or without low-dose ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection and severe renal impairment (RI) are limited. We evaluated the performance of SOF/VEL with or without low-dose RBV in HCV-infected patients with chronic kidney disease stage 4 or 5. DESIGN: 191 patients with compensated (n=181) and decompensated (n=10) liver diseases receiving SOF/VEL (400/100 mg/day) alone and SOF/VEL with low-dose RBV (200 mg/day) for 12 weeks were retrospectively recruited at 15 academic centres in Taiwan. The effectiveness was determined by sustained virological response at off-treatment week 12 (SVR12) in evaluable (EP) and per-protocol populations (PP). The safety profiles were assessed. RESULTS: The SVR12 rates by EP and PP analyses were 94.8% (95% CI 90.6% to 97.1%) and 100% (95% CI 97.9% to 100%). In patients with compensated liver disease, the SVR12 rates were 95.0% and 100% by EP and PP analyses. In patients with decompensated liver disease, the SVR12 rates were 90.0% and 100% by EP and PP analyses. Ten patients who failed to achieve SVR12 were attributed to non-virological failures. Among the 20 serious adverse events (AEs), none were judged related to SOF/VEL or RBV. The AEs occurring in ≥10% included fatigue (14.7%), headache (14.1%), nausea (12.6%), insomnia (12.0%) and pruritus (10.5%). None had ≥grade 3 total bilirubin or alanine aminotransferase elevations. CONCLUSION: SOF/VEL with or without low-dose RBV is effective and well-tolerated in HCV-infected patients with severe RI.

Impact of Sofosbuvir-Based Direct-Acting Antivirals on Renal Function in Chronic Hepatitis C Patients With Impaired Renal Function: A Large Cohort Study From the Nationwide HCV Registry Program (TACR).

BACKGROUND & AIMS: Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world nationwide basis is elusive. METHODS: The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non-sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT). RESULTS: The eGFR decreased from baseline (91.4 mL/min/1.73 m2) to EOT (88.4 mL/min/1.73 m2; P < .001) and substantially recovered at EOF (88.8 mL/min/1.73 m2) but did not return to pretreatment levels (P < .001). Notably, a significant decrease in eGFR was observed only in patients with baseline eGFR ≥90 mL/min/1.73 m2 (from 112.9 to 106.4 mL/min/1.73 m2; P < .001). In contrast, eGFR increased progressively in patients whose baseline eGFR was <90 mL/min/1.73 m2 (from 70.0 to 71.5 mL/min/1.73 m2; P < .001), and this increase was generalized across different stages of CKD. The trend of eGFR amelioration was consistent irrespective of sofosbuvir usage. Multivariate adjusted analysis demonstrated that baseline eGFR >90 mL/min/1.73 m2 was the only factor independently associated with significant slope coefficient differences of eGFR (-1.98 mL/min/1.73 m2; 95% confidence interval, -2.24 to -1.72; P < .001). The use of sofosbuvir was not an independent factor associated with eGFR change. CONCLUSIONS: Both sofosbuvir and non-sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.

The effect of coffee/caffeine on postoperative ileus following elective colorectal surgery: a meta-analysis of randomized controlled trials.

PURPOSE: Postoperative ileus (POI) is the most common complication of elective colon resection. Coffee or caffeine has been reported to be useful in improving gastrointestinal function after abdominal surgery. This study aimed to investigate the effect of coffee/caffeine on POI in patients undergoing elective colorectal surgery. METHODS: We searched Cochrane library, Embase, PubMed, and ClinicalTrials.gov (until July 2021) to identify randomized controlled trials (RCTs) evaluating the effect of coffee or caffeine on bowel movements and POI in patients undergoing elective colorectal surgery. The mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes were calculated and are presented with 95% confidence intervals (CIs). A random effects model was used in all meta-analyses. RESULTS: A total of four RCTs including 312 subjects met the inclusion criteria and were included in the meta-analysis. Postoperative coffee or caffeine consumption decreased the time to first bowel movement (MD, - 10.36 h; 95% CI, - 14.61 to - 6.11), shortened the length of hospital stay (MD, - 0.95 days; 95% CI, - 1.57 to - 0.34), and was associated with a decreased risk of the use of any laxatives after the procedure (RR, 0.64; 95% CI, 0.44 to 0.92). The time to first flatus, time to tolerance of solid food, risk of any postoperative complication, postoperative reinsertion of a nasogastric (NG) tube, and anastomotic leakage showed no statistical differences between groups. CONCLUSION: Postoperative coffee or caffeine consumption improved bowel movement and decreased the duration of hospital stay in patients undergoing elective colorectal surgery. This method is safe and can prevent or treat POI.

Intragastric injection of botulinum toxin A for weight loss: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Intragastric botulinum toxin A (BTA) injection is a potential treatment for weight reduction in obese patients. Current studies yielded conflicting results. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy of intragastric BTA injection for weight management. METHODS: We searched several databases to identify RCTs evaluating intragastric BTA injections for obesity. We applied random-effects models for all meta-analyses due to heterogeneity in the included studies. The mean difference (MD) and 95% confidence interval (CI) were calculated for continuous outcomes. RESULTS: A total of 6 RCTs including 192 subjects met the inclusion criteria and were included for the meta-analysis. Although the pooled data from six studies showed no difference in the absolute weight loss between intragastric BTA injection and control, subgroup analysis showed a significantly decreased absolute weight after a BTA injection dose ≥ 200 U (MD, -2.04 kg; 95% CI, -3.96 to -0.12) and after multiple injection regions in the stomach combined with diet control (MD, -4.44 kg; 95% CI, -6.54 to -2.33 kg) compared with the control. Regarding absolute weight loss, the impact of endoscopic ultrasound-guided injection and follow-up duration showed no difference. Intragastric BTA injection had a significant change in body mass index (MD, -1.25 kg/m2 ; 95% CI, -2.18 to -0.32 kg/m2 ) and prolonged gastric half-emptying time (MD, 11.37 min; 95% CI, -3.69 to 19.06 min). CONCLUSION: Intragastric BTA injection is effective for obesity treatment, and adequate doses (≥ 200 U), multiple gastric injection regions, and combined diet control are crucial. However, given the small sample size and limited power, caution should be exercised.