Efficacy of Prednisone Avoidance in Patients With Liver Transplant Using the U.S. Food and Drug Administration Adverse Event Reporting System.

Background Immunosuppressants are administered in various combinations to prevent immune-induced transplant rejection in patients with liver transplant, as each immunosuppressant acts on different cellular sites. However, the use of multiple immunosuppressants also increases the risk for adverse events. Therefore, it is desirable to reduce the types of immunosuppressants administered without increasing the incidence of transplant rejection. The effectiveness of prednisone avoidance has been suggested, although this was not based on statistical significance in many instances. To definitively establish the effectiveness of prednisone avoidance, a statistically significant difference from a prednisone-use group should be demonstrated. Additionally, the effectiveness of prednisone avoidance might vary depending on the combination of other immunosuppressants administered. It has therefore been considered necessary to investigate, for various immunosuppressant combinations, the administration patterns in which prednisone avoidance is effective. Objectives This study aimed to investigate the effectiveness of prednisone avoidance in patients with liver transplant and discuss the results based on statistically significant differences. Methods Data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) were obtained. In studying immunosuppressant combinations, it was essential to control for confounding. Thus, the immunosuppressant combinations, excluding prednisone, were kept the same in the two groups being compared (prednisone-use and prednisone-avoidance groups). The large sample from FAERS allowed for those various immunosuppressant combinations to be compared. Comparisons of transplant rejection in the prednisone-use and prednisone-avoidance groups used the reporting odds ratio (ROR) and the adjusted ROR (aROR), which controlled for differences in patient background. Results With the prednisone-use groups being set as the reference, ROR and aROR were calculated for the prednisone-avoidance groups. Various immunosuppressant combinations were evaluated, and in four patterns - (1) the combination of prednisone and tacrolimus, (2) the combination of prednisone, cyclosporine, and tacrolimus, (3) the combination of prednisone, tacrolimus, and basiliximab, and (4) the combination of prednisone and everolimus) - both the ROR and the aROR for transplant rejection in the prednisone-avoidance group were significantly <1.000. Conclusions This study identified effective immunosuppressant combinations for prednisone avoidance that were not associated with increased transplant rejection. The evidence supporting the effectiveness of prednisone avoidance is strengthened when combined with results from previous studies.

Diagnostic performance of fluoroscopic video analysis for pulmonary embolism: a prospective observational study.

PURPOSE: Dynamic chest radiography using X-ray fluoroscopic video analysis has shown potential for the diagnosis of pulmonary embolism (PE), but its diagnostic performance remains uncertain. We aimed to evaluate the diagnostic performance of fluoroscopic video analysis for diagnosing PE. METHODS: A prospective single-center observational study was conducted between October 2020 and January 2022. Fifty consecutive adult patients, comprising definitive PE, pulmonary hypertension (PH), or suspected PH, were enrolled. The study population was classified into 23 PE and 27 non-PE cases by contrast-enhanced computed tomography, lung scintigraphy, right heart catheterization, and pulmonary angiography. Cineradiographic images of 10-second breath-holds were obtained and analyzed using a fluoroscopic video analysis workstation to generate pulmonary circulation images. Two blinded cardiologists qualitatively assessed the presence or absence of perfusion defects on the pulmonary circulation images. The diagnosis obtained from the fluoroscopic analysis was compared with the definitive diagnosis. The primary outcomes included sensitivity, specificity, positive and negative predictive values, and overall accuracy for diagnosing PE. RESULTS: Perfusion defects were observed in 21 of 23 PE patients and 13 of 27 non-PE patients. The diagnostic performance of fluoroscopic video analysis for diagnosing PE showed a sensitivity of 91%, specificity of 52%, positive predictive value of 62%, negative predictive value of 88%, and overall accuracy of 70%. CONCLUSIONS: The high sensitivity of the fluoroscopic video analysis suggests its potential usefulness in ruling out PE without the need for contrast media or radionuclide; however, its specificity and overall accuracy remain limited.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants for Japanese Patients With Venous Thromboembolism　- The Primary Results From the KUROSIO Study.

BACKGROUND: Direct oral anticoagulants (DOACs) are recommended as the first-choice anticoagulation therapy in the acute phase of venous thromboembolism (VTE). However, there is limited real-world data for Japanese VTE patients.Methods and Results: The KUROSIO study (UMIN000023747) was a prospective long-term observational study comprising 1,017 patients with concurrent acute symptomatic pulmonary thromboembolism and proximal deep vein thrombosis (DVT) or isolated calf DVT initially treated with DOACs. After excluding 24 patients, 993 (mean age, 66.3±15.1 years; 58.6% females) were analyzed. The incidences of recurrent symptomatic VTE and major bleeding for up to 52 weeks after diagnosis were 3.2% and 2.2%, respectively. Multivariate analyses revealed chemotherapy and anemia as significant risk factors associated with recurrent symptomatic VTE and major bleeding, respectively. CONCLUSIONS: The efficacy and safety of DOACs in Japanese patients with VTE were determined in this real-world observational study.

[Evaluation of Pharmacy Students' Understanding of Clinical Trials and Research through Questionnaires Before and After the Hospital Practical Training].

A questionnaire survey was conducted to evaluate practical training and improve education on clinical trial and research. This survey was based on the results of questionnaire before and after the practical training undertaken by 240 pharmaceutical students (Kanto region; 1 university, Tokai region; 2 university, Kinki region; 9 university) at Mie University Hospital between 2011 and 2022. In the questionnaire before practical training, lectures in university (n=219, 91%) were the main source of information on clinical trials and research. Fifty-two students (22%) correctly answered the contents of phase 1-4 trials. As an occupation that can perform clinical research coordinator (CRC)'s work, only 7 students (3%) answered that "all medical and non-medical professionals" can perform the CRC's duties. Regarding the understanding of terms related to clinical trials and research, more than 90% of the students understood the meaning of "subjects," "informed consent," and "placebo" even before practical training. Otherwise, even after practical training, students' understanding of "reimbursement," "follow-up period," "audit," or "direct access" was less than 80%. Practical training improved the understanding of terms such as clinical trial (Wilcoxon signed-rank test, p<0.001), clinical research phase 1-4 trials (Wilcoxon signed-rank test, p<0.001), interest in clinical trials and research (McNemar-Bowker test, p<0.001), and understanding of CRC's work (McNemar-Bowker test, p<0.001). We will improve the content of practical training and bequeath the knowledge and importance of drug discovery and development to the next generation.

Risk stratification for synchronous/metachronous recurrence after endoscopic submucosal dissection for Barrett's esophageal adenocarcinoma using the length of Barrett's esophagus.

BACKGROUND: In Japan, the standard management of Barrett's esophageal adenocarcinoma after endoscopic submucosal dissection involves follow-up; however, multifocal synchronous/metachronous lesions are sometimes observed after endoscopic submucosal dissection. Risk stratification of multifocal cancer facilitates appropriate treatment, including eradication of Barrett's esophagus in high-risk cases; however, no effective risk stratification methods have been established. Thus, we identified the risk factors for multifocal cancer and explored risk-stratified treatment strategies for residual Barrett's esophagus. METHODS: We retrospectively reviewed the data of 97 consecutive patients with superficial Barrett's esophageal adenocarcinomas who underwent curative resection with endoscopic submucosal dissection. Multifocal cancer was defined by the presence of synchronous/metachronous lesions during follow-up. We used Cox regression analysis to identify the risk factors for multifocal cancer and subsequently analyzed differences in cumulative incidences. RESULTS: The cumulative incidences of multifocal cancer at 1, 3, and 5 years were 4.4%, 8.6%, and 10.7%, respectively. Significant risk factors for multifocal cancer were increased circumferential and maximal lengths of Barrett's esophagus. The cumulative incidences of multifocal cancer at 3 years were lower for patients with circumferential length < 4 cm and maximal length < 5 cm (2.9% and 1.2%, respectively) than for patients with circumferential length ≥ 4 cm and maximal length ≥ 5 cm (51.5% and 49.1%, respectively). CONCLUSIONS: Risk stratification of multifocal cancer using length of Barrett's esophagus was effective. Further multicenter prospective studies are needed to substantiate our findings.

Analysis of Adverse Events Following Phenobarbital Administration for Pediatric Patients Categorized by One-Year Age Increments Using the U.S. Food and Drug Administration Adverse Event Reporting System.

Background Organ and body development greatly varies in pediatric patients from year to year. Therefore, the incidence of each adverse event following phenobarbital (PB) administration would vary with age. However, in clinical trials, increasing the sample size of pediatric patients in each age group has been challenging. Therefore, previous studies were conducted by dividing pediatric patients into three or four age groups based on the development stage. Although these results were useful in clinical settings, information on adverse events that occurred at one-year age increments in pediatric patients could further enhance treatment and care. Objectives This study investigated in one-year age increments the occurrence tendency of each adverse event following PB administration in pediatric patients. Methods This study used data obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Two inclusion criteria were set: (1) treatment with PB between January 2004 and June 2023 and (2) age 0-15 years. Using the cutoff value obtained using the Wilcoxon-Mann-Whitney test by the minimum p-value approach, this study explored changes in the occurrence tendency of each adverse event in one-year age increments. At the minimum p-value of <0.05, the age corresponding to this p-value was determined as the cutoff value. Conversely, at the minimum p-value of ≥0.05, the cutoff value was considered nonexistent. Results This study investigated all types of adverse events and explored the cutoff value for each adverse event. We identified 34, 16, 15, nine, five, five, eight, three, and eight types of adverse events for the cutoff values of ≤3/>3, ≤4/>4, ≤5/>5, ≤6/>6, ≤7/>7, ≤8/>8, ≤9/>9, ≤10/>10, and ≤11/>11 years, respectively. Conclusions This study demonstrated that adverse events requiring attention in pediatric patients varied with age. The findings help in the improvement of treatment and care in the pediatric clinical settings.

Prevalence and risk factors of ankle osteoarthritis in a population-based study.

BACKGROUND: This study aimed to investigate the prevalence of radiographic ankle osteoarthritis (AOA) in Japan and identify its risk factors. METHODS: The analysis included data from the population-based cohort study, radiographs of the knees and ankles, ultrasonography of the ankle to examine chronic ankle instability (CAI), and questionnaires on ankle pain, job history, height, and body weight. A total of 597 individuals aged > 50 years were included in the study. The risk factors for AOA were calculated using multivariate logistic regression analysis. RESULTS: The study revealed a 13.9% prevalence of radiographic AOA among the participants, with 1.2% reporting painful AOA. Female sex, aging, history of ankle fractures, and CAI were identified as the risk factors associated with AOA. CONCLUSIONS: This cross-sectional study highlights the significant prevalence of radiographic AOA in a rural Japanese population, emphasizing the importance of considering ankle fractures and CAI as potential risk factors for AOA development. LEVELS OF EVIDENCE: Level II, prospective cohort study.

Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Analysis of death avoidance by concomitant use of prednisone in patients with renal transplant using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Patients with renal transplant are frequently administered immunosuppressants to prevent transplant-related adverse events. There are mainly nine immunosuppressants on the market, and multiple immunosuppressants are frequently administered for patients with renal transplant. Identifying which immunosuppressant was responsible when efficacy or safety was observed in patients taking multiple immunosuppressants is difficult. This study aimed to identify the immunosuppressant that was effective in reducing death in patients with renal transplant. A very large sample size was required to conduct prospective clinical trials of immunosuppressant combinations, which is impractical. We investigated cases wherein death occurred despite immunosuppressant administration in patients with renal transplant using Food and Drug Administration Adverse Event Reporting System (FAERS) data. MATERIAL AND METHOD: We used FAERS data reported between January 2004 and December 2022 in patients with renal transplant who received one or more immunosuppressants. Groups were defined for each combination of immunosuppressants. Comparison between two identical groups except for the presence or absence of prednisone was performed using the reporting odds ratio (ROR) and the adjusted ROR (aROR) controlling for differences in patient background. RESULTS: When the group without prednisone was set as the reference, the aROR for death was significantly <1.000 in several cases in the group to which prednisone was added. CONCLUSIONS: The inclusion of prednisone in the immunosuppressant combinations was suggested to be effective in reducing death. We provided the sample code of software R that can reproduce the results.

The usefulness of image-enhanced endoscopy to distinguish gastric carcinoma in tumors initially diagnosed as adenomas by endoscopic biopsy: A retrospective study.

Superficial epithelial gastric neoplasms can be divided into adenomas and early carcinomas. Histological diagnosis by endoscopic forceps biopsy is crucial for the diagnosis and management of gastric neoplasms. It is difficult to distinguish features of gastric neoplasms in small biopsy specimens; hence, gastric carcinomas can be underdiagnosed as adenomas. Recent developments in image-enhanced endoscopy have improved the ability to differentiate between carcinomatous and non-carcinomatous lesions. To investigate the prevalence of gastric carcinoma in lesions initially diagnosed as adenomas by forceps biopsy and assess the usefulness of image-enhanced endoscopy in distinguishing carcinomas. A total of 142 lesions of gastric adenomas, diagnosed by biopsy and resected endoscopically between January 2010 and May 2020, were retrospectively evaluated. Images were captured by white-light endoscopy (WLE), magnifying endoscopy with narrow-band imaging (M-NBI), and magnifying endoscopy with acetic acid and narrow-band imaging (M-AANBI); they were analyzed and compared with histopathological results. The diagnostic performance of M-AANBI was compared with that of M-NBI. Of the 142 lesions, 58 (40.8%) were pathologically diagnosed as adenocarcinomas. On WLE images, a depressed macroscopic type and size ≥20 mm were significant predictors of carcinoma (P < .001); however, they displayed low sensitivities (32.8% and 41.4%, respectively). M-AANBI displayed significantly higher sensitivity, specificity, and accuracy for distinguishing carcinomas than M-NBI (94.8% vs 74.1%, 81.0% vs 72.6%, and 86.6% vs 73.2%, P < .05). In conclusion, carcinoma was prevalent in 40.8% of gastric lesions initially diagnosed as adenomas by forceps biopsy. M-AANBI may be more useful than M-NBI and WLE in distinguishing gastric carcinomas from adenomas.

Comparison of Adverse Events Occurred During Administration of Dipeptidyl Peptidase-4 Inhibitor in Patients with Diabetes Using FDA Adverse Event Reporting System.

BACKGROUND AND OBJECTIVE: Various dipeptidyl peptidase-4 (DPP-4) inhibitors have been approved for the treatment of diabetes. The frequencies of known serious side effects might differ among DPP-4 inhibitors, therefore a large sample size is needed to study them in prospective clinical trials. We examined the adverse events that occurred during the administration of a DPP-4 inhibitor in patients with diabetes using FDA Adverse Event Reporting System (FAERS) data. METHODS: We used FAERS data reported between January 2013 and March 2022 in patients with diabetes who received a DPP-4 inhibitor. Statistical analyses were conducted to calculate reporting odds ratio (ROR) and adjusted ROR (aROR) controlling for differences in patient background. RESULTS: The 9 target DPP-4 inhibitors were sitagliptin (N = 26,843), vildagliptin (N = 4767), alogliptin (N = 2085), linagliptin (N = 7969), saxagliptin (N = 3334), teneligliptin (N = 461), anagliptin (N = 102), trelagliptin (N = 17), and omarigliptin (N = 12). Compared with sitagliptin, aROR of acute kidney injury was significantly < 1.000 for alogliptin (0.247 [95% confidence interval (CI) 0.150-0.408], p < 0.001) but aROR of pemphigoid was significantly > 1.000 for alogliptin (3.082 [95% CI 2.156-4.406], p < 0.001). Similar statistical analyses were conducted for other adverse events and the types of adverse events with aROR of significantly < 1.000 or > 1.000 differed depending on the type of DPP-4 inhibitor. CONCLUSIONS: Although it is impossible to select a DPP-4 inhibitor with aROR of < 1.000 of all occurrences of adverse events, these results may be used for drug selection when the patient has adverse events that need to be avoided. We provided the sample code of software R that can reproduce the results.

Hyperkalemia by eplerenone or esaxerenone in the presence or absence of clarithromycin in hypertensive patients: a retrospective observational cohort study.

OBJECTIVE: Mineralocorticoid receptor antagonists (MRAs), eplerenone and esaxerenone, cause hyperkalemia dose-dependently. We investigated the cytochrome P450 3A4-mediated drug-drug interaction between the MRAs and clarithromycin. METHODS: This retrospective observational study included adult hypertensive patients with MRA plus clarithromycin or MRA alone with a propensity score matching (1:1). The difference in serum potassium level (ΔK, maximum level - baseline level) between groups was compared using the Mann-Whitney U -test. Linear regression analysis was used to detect variables that correlated with ΔK in patients with MRA plus clarithromycin. RESULTS: After propensity score matching (each nine patients), serum potassium level was elevated after treatment with MRA plus clarithromycin [4.3 (3.5 to 5.1) meq/l to 4.9 (4.0 to 5.5) meq/l, P  = 0.0234] and MRA alone [4.3 (4.0 to 4.7) meq/l to 4.6 (4.4 to 5.2) meq/l, P  = 0.0469]. Although there was no significant difference in ΔK between groups [MRA plus clarithromycin: 0.5 (0.1 to 1.1) meq/l vs. MRA alone: 0.3 (0.1 to 1.2) meq/l, P  = 0.7231], ΔK was significantly higher in esaxerenone plus clarithromycin than in esaxerenone alone [0.6 (0.5 to 1.1) meq/l vs. 0.1 (0.1 to 0.2) meq/l, P  = 0.0495]. Conversely, clarithromycin did not show a significant effect on ΔK in patients with eplerenone [0.4 (-0.2 to 1.2) meq/l vs. 0.8 (0.1 to 1.3) meq/l, P  = 0.5745]. A positive correlation was found between ΔK and age in patients with MRA plus clarithromycin ( y  = 0.03 ×  x - 1.38, r  = 0.71, P  = 0.0336). CONCLUSION: The drug-drug interaction between MRAs and clarithromycin was evident, particularly in esaxerenone. Serum potassium levels should be closely monitored in older patients.

Analysis of Clinical Factors in Olaparib-related Anemia Using Adverse Drug Event Reporting Databases.

BACKGROUND/AIM: Anemia is one of the dose-limiting toxicities of olaparib. A global randomized controlled trial confirmed that anemia occurrence in Japanese was relatively high. The factors related to anemia in different nationalities remain unknown. Therefore, this study investigated the factors of olaparib-related anemia in real-world settings using an adverse event reporting system database. PATIENTS AND METHODS: We used data from FDA Adverse Events Reporting System (FAERS) and Japanese Adverse Drug Event Report database (JADER) between 2018 and 2021. FAERS reports from Japan were collected to conduct subgroup analysis, which was defined as FAERS-Japan. The endpoint was the occurrence of olaparib-related anemia. Disproportionality analysis was conducted to calculate reporting odds ratio (ROR), with a confidence interval of 95%. Adjusted ROR (aROR) was calculated to control for sex differences. RESULTS: In FAERS and JADER, the daily olaparib dose per body weight (DPBW) ≥12 mg/kg was associated with anemia occurrence [aROR; FAERS, 4.483 (3.009-6.680), p<0.001, FAERS-Japan, 1.834 (1.091-3.063), p=0.009, and JADER, 1.628 (1.039-2.551), p=0.034]. Furthermore, FAERS reports confirmed that females with body weight <50 kg, reports from Japan, concomitant use of drugs causing vitamin B12 deficiency, and previous platinum treatment history were associated with olaparib-related anemia. FAERS-Japan also showed that body weight <50 kg and previous platinum treatment history were associated with anemia occurrence. CONCLUSION: High DPBW constitutes a significant risk of olaparib-related anemia. In addition, information on co-administration of drugs causing vitamin B12 deficiency and previous platinum treatment history is also important for the evaluation of the risk of olaparib-related anemia.

Parameter estimation of Weibull distribution for the number of days between drug administration and early onset adverse event.

The Weibull distribution is applied to the number of days between the start date of drug administration and the date of occurrence of an adverse event. The tendency of occurrence of adverse events can be clarified by estimating the two- or three-parameter Weibull distribution, using the data regarding the number of days. Our purpose is to estimate the parameters of the Weibull distribution with high accuracy, even in low-reported adverse events, such as new drugs, polypharmacy and small clinical trials. Furthermore, the two-sample Kolmogorov - Smirnov test (two-sided) is used to examine whether the tendency of occurrence of adverse events is different for two Weibull distributions estimated from two drugs with similar efficacy. We used discrete data derived from FDA Adverse Event Reporting System (FAERS), as the FAERS data are presented in years, months and days without hours and minutes. Because this study focuses on early onset adverse events, data may be contained 0 days. The discreteness of the data and the fact that it may include zero make this distribution different from the general Weibull distribution, which is defined for continuous data greater than zero. We search for the optimal parameter estimation method for the Weibull distribution under these two conditions, and verify its effectiveness using Monte Carlo simulations and FAERS data. Because the results obtained from FAERS data may differ depending on data handling, we describe the of data handling technique and the sample code that can reproduce the results.

Psychological characteristics of Japanese patients and their family members receiving genetic counseling: A single-institute exploratory study.

In Japan, clinical genetic services became available in the 1970s, and genomic medicine, including genetic counseling (GC), developed rapidly. However, research on the outcomes of GC in Japan is limited. Japan has a unique cultural context, and appropriate GC methods have not yet been optimized for this population. The current study aimed to evaluate the psychological status of Japanese patients and their companions undergoing GC and the outcomes of GC. We used the Quality of Care Through the Patients' Eyes-gene cancer (QUOTE-geneCA ), the Genetic Counseling Outcome Scale-24 (GCOS-24), and the State-Trait Anxiety Inventory (STAI) to evaluate patients and their companions' needs and preferences regarding GC, empowerment, and anxiety, respectively. We evaluated stress status during GC by measuring saliva cortisol levels. QUOTE-geneCA results for patients (n = 69) and a group of patients and their companions (n = 96) revealed that participants felt that it was important that skilled medical staff explained medical information and provided advice in an easily understandable manner. Japanese patients and their companions regarded the procedural aspects of counseling as most important and their autonomy in decision-making as less important. GCOS-24 results revealed a significant increase in empowerment scores in 38 patients (by 9.63 points) from pre- to post-GC (p < 0.001; Cohen's d = 0.79). STAI results revealed a significant decrease in state anxiety for patients (6.11 points; p < 0.001; Cohen's d = 0.66). Cortisol levels in patients significantly decreased after GC (p = 0.001). The improvement of empowerment scores from pre- to post-GC among patients and their companions were significantly negatively correlated with pre-GC empowerment scores (p < 0.001), trait anxiety scores (p = 0.001), and the number of people living together (p = 0.011). The change of cortisol levels during GC in patients and their companions was significantly positively correlated with trait anxiety score (p = 0.027). This study suggested that these characteristics of Japanese patients and their companions may predict GC outcomes.

Tadalafil treatment for fetuses with early-onset growth restriction: a protocol for a multicentre, randomised, placebo-controlled, double-blind phase II trial (TADAFER IIb).

INTRODUCTION: TheTADAlafil treatment for Fetuses with early-onset growth Restriction: multicentrer, randomizsed, phase II trial (TADAFER II) study showed the possibility of prolonging the pregnancy period in cases of early-onset fetal growth restriction; however, it was an open-label study. To establish further evidence for the efficacy of tadalafil in this setting, we planned a multicentre, randomised, placebo-controlled, double-blind trial. METHODS AND ANALYSIS: This trial will be conducted in 180 fetuses with fetal growth restriction enrolled from medical centres in Japan; their mothers will be randomised into three groups: arm A, receiving two times per day placebo; arm B, receiving one time per day 20 mg tadalafil and one time per day placebo and arm C, receiving 20 mg two times per day tadalafil. The primary endpoint is the prolongation of gestational age at birth, defined as days from the first day of the protocol-defined treatment to birth. To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery as in TADAFER II will be established in this trial. The investigator will evaluate fetal baseline conditions at enrolment and decide the timing of delivery based on this indication. ETHICS AND DISSEMINATION: This study has been approved by Mie University Hospital Clinical Research Review Board on 22 July 2019 (S2018-007). Written informed consent will be obtained from all mothers before recruitment. Our findings will be widely disseminated through peer-reviewed publications. TRIAL REGISTRATION: jRCTs041190065.

Predictive risk factors for early recurrence in patients with localized pancreatic ductal adenocarcinoma who underwent curative-intent resection after preoperative chemoradiotherapy.

BACKGROUND: The optimal surgical indication after preoperative chemoradiotherapy (CRT) remains a subject of debate for patients with pancreatic ductal adenocarcinoma (PDAC) because early recurrence often occurs even after curative-intent resection. The present study aimed to identify perioperative risk factors of early recurrence for patients with PDAC who underwent curative-intent resection after preoperative CRT. METHODS: Two hundred three patients with PDAC who underwent curative-intent resection after preoperative CRT from February 2005 to December 2018 were retrospectively analyzed. The optimal threshold for differentiating between early and late recurrence was determined by the minimum p-value approach. Multivariate regression analysis was performed to identify predictive factors for early recurrence. RESULTS: In 130 patients who developed recurrence after resection, 52 who had an initial recurrence within 12 months were defined as the early recurrence group, and the remaining 78 were defined as the late recurrence group. The incidence of hepatic recurrence was significantly higher in the early recurrence group than in the late recurrence group (39.7 vs. 15.4%). The early recurrence group had significantly lower 3-year rates of post-recurrence and overall survival than the late recurrence group (4.0 and 10.7% vs. 9.8 and 59.0%, respectively). Serum level of CA19-9 before surgery ≥56.8 U/ml was identified as an independent risk factor for early recurrence (OR:3.07, 95%CI:1.65-5.73, p<0.001) and associated with a significantly higher cumulative incidence rate of hepatic recurrence and lower rates of recurrence-free and overall survival. CONCLUSION: Serum level of CA19-9 before surgery after preoperative CRT was a strong predictive factor for early recurrence.

Platelet-Rich Plasma Releasate versus Corticosteroid for the Treatment of Discogenic Low Back Pain: A Double-Blind Randomized Controlled Trial.

Clinical application of platelet-rich plasma is gaining popularity in treating low back pain (LBP). This study investigated the efficacy and safety of platelet-rich plasma releasate (PRPr) injection into degenerated discs of patients with discogenic LBP. A randomized, double-blind, active-controlled clinical trial was conducted. Sixteen patients with discogenic LBP received an intradiscal injection of either autologous PRPr or corticosteroid (CS). Patients in both groups who wished to have PRPr treatment received an optional injection of PRPr eight weeks later. The primary outcome was change in VAS from baseline at eight weeks. Secondary outcomes were pain, disability, quality of life (QOL), image analyses of disc degeneration, and safety for up to 60 weeks. The VAS change at eight weeks did not significantly differ between the two groups. Fifteen patients received the optional injection. Compared to the CS group, the PRPr group had a significantly improved disability score at 26 weeks and walking ability scores at four and eight weeks. Radiographic disc height and MRI grading score were unchanged from baseline. PRPr caused no clinically important adverse events. PRPr injection showed clinically significant improvements in LBP intensity equal to that of CS. PRPr treatment relieved pain, and improved disability and QOL during 60 weeks of observation.

Is locomotion training effective for middle-aged workers?

OBJECTIVES: Locomotion training (LT) consisting of single-leg standing and squatting was developed to help prevent locomotive syndrome (LS), and is typically used in older people. The objective of this study was to examine the effects of LT on young and middle-aged people. METHODS: This study was performed at two companies. Workers in company A engaged in LT five times/week for 1 year, whereas workers in company B did not. Baseline and follow-up checkups consisted of questionnaires and physical performance tests, including three kinds of locomotion tests. RESULTS: In total, 88 and 101 workers in companies A and B, respectively, met the inclusion criteria. LS stage, stand-up test results, and scores on a geriatric locomotive function scale significantly improved among workers in company A, but only stand-up test results significantly improved among workers in company B. Quadriceps power increased in company A, but did not change in company B. Especially, workers with LS in company A had more significant changes than those without LS and those in company B. CONCLUSIONS: The results of this longitudinal study suggest that LT is useful even for young and middle-aged workers. LT was especially more effective for workers than those without LS.

Improving the Prognosis of Pancreatic Cancer Through Early Detection: Protocol for a Prospective Observational Study.

BACKGROUND: Pancreatic cancer is associated with high mortality and its rates of detection are very low; as such, the disease is typically diagnosed at an advanced stage. A number of risk factors for pancreatic cancer have been reported and may be used to identify individuals at high risk for the development of this disease. OBJECTIVE: The aim of this prospective, observational trial is to evaluate a scoring metric for systematic early detection of pancreatic cancer in Mie Prefecture, Japan. METHODS: Eligible patients aged 20 years and older will be referred from participating clinics in the Tsu City area to the Faculty of Medicine, Gastroenterology, and Hepatology at Mie University Graduate School, until September 30, 2022. Participants will undergo a detailed examination for pancreatic cancer. Data collection will include diagnostic and follow-up imaging data and disease staging information. RESULTS: The study was initiated in September 2020 and aims to recruit at least 150 patients in a 2-year period. Recruitment of patients is currently still underway. Final data analysis is expected to be complete by March 2025. CONCLUSIONS: This study will provide insights into the feasibility of using a scoring system for the early detection of pancreatic cancer, thus potentially improving the survival outcomes of diagnosed patients. TRIAL REGISTRATION: UMIN-CTR Clinical Trials Registry UMIN000041624; https://tinyurl.com/94tbbn3s. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/26898.