Effect of Luseogliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, and Dipeptidyl-Peptidase 4 Inhibitors on the Quality-of-Life and Treatment Satisfaction of Patients With Type 2 Diabetes Mellitus: A Subanalysis of a Multicenter, Open-Label, Randomized-Controlled Trial (J-SELECT Study).

INTRODUCTION: The effects of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) on quality of life (QOL) and treatment satisfaction have not been directly compared. This sub-analysis of a randomized-controlled trial with an SGLT2i, luseogliflozin, and DPP-4is compared their effects on QOL and treatment satisfaction of patients. METHODS: This study recruited 623 patients with type 2 diabetes mellitus who were drug-naïve or treated with antidiabetic agents other than SGLT2is and DPP-4is. The patients were randomized into luseogliflozin or DPP-4i group and followed for 52 weeks. This sub-analysis assessed QOL and treatment satisfaction using Oral Hypoglycemic Agent Questionnaire (OHA-Q) version 2 in the drug-naïve subgroup who were drug-naïve at baseline and with monotherapy with luseogliflozin or DPP-4i throughout the observation period (256 patients) at 24 and 52 weeks and in the add-on subgroup who were treated with OHAs other than SGLT2is and DPP-4is (204 patients) at baseline, 24 and 52 weeks. RESULTS: In the drug-naïve subgroup, total (50.8 ± 8.2 in luseogliflozin group and 53.1 ± 10.0 in DPP-4i group, p = 0.048) and somatic symptom scores (22.4 ± 5.0 in luseogliflozin group and 24.4 ± 5.8 in DPP-4i group, p = 0.005) at 52 weeks (but not at 24 weeks) were significantly higher in DPP-4i group than in luseogliflozin group. In add-on subgroup, changes in total (3.3 ± 7.8 in luseogliflozin group and 0.9 ± 7.6 in DPP-4i group, p = 0.030) and treatment convenience (1.2 ± 3.9 in luseogliflozin group and - 0.6 ± 4.2 in DPP-4i group, p = 0.002) from baseline to 24 weeks (but not at 52 weeks) were significantly greater in luseogliflozin group than in DPP-4i group. The QOL related to safety or glycemic control was comparable between the groups. CONCLUSIONS: Physicians should pay attention to side effects of SGLT2is to maintain the patients' QOL when SGLT2is are initiated or added-on. Add-on of luseogliflozin increased patients' QOL more than DPP-4is. Considering patients' QOL and treatment satisfaction is important for selecting SGLT2is or DPP-4is. TRIAL REGISTRATION: UMIN000030128 and jRCTs031180241.

Development and Evaluation of "The Delta Plus-Minus Even Distribution Check": A Novel Patient-Based Real-Time Quality Control Method for Laboratory Tests.

BACKGROUND: Laboratory testing of large sample numbers necessitates high-volume rapid processing, and these test results require immediate validation and a high level of quality assurance. Therefore, real-time quality control including delta checking is an important issue. Delta checking is a process of identifying errors in individual patient results by reviewing differences from previous results of the same patient (Δ value). Under stable analytical conditions, Δ values are equally positively and negatively distributed. METHODS: The previous 20 Δ values from 3 tests (cholesterol, albumin, and urea nitrogen) were analyzed by calculating the R-value: "the positive Δ value ratio minus 0.5." This method of monitoring optimized R-values is referred to as the even-check method (ECM) and was compared with quality control (QC) testing in terms of error detection. RESULTS: Bias was observed on 4 of the 120 days for the 3 analytes measured. When QC detected errors, the ECM captured the same systematic errors and more rapidly. In contrast, the ECM did not generate an alarm for the one random error that occurred in QC. While QC did not detect any errors, the percentage of R-values exceeding the acceptable range was under 2%, the number of days generating alarms was between 16 and 21 days, with short alarm periods, and a median number of samples per alarm period between 7 and 9 samples. CONCLUSIONS: The ECM is a practical real-time QC method, controlled by setting R-value conditions, that quickly detects bias values.

Efficacy and safety of lascufloxacin for nursing- and healthcare-associated pneumonia: A single-arm, open-label clinical trial.

BACKGROUND: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. METHODS: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. RESULT: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. CONCLUSION: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications.

Overall Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin Versus Dipeptidyl-Peptidase 4 Inhibitors: Multicenter, Open-Label, Randomized-Controlled Trial (J-SELECT study).

INTRODUCTION: Evidence of a direct comparison between dipeptidyl-peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) remains lacking, and no clear treatment strategy or rationale has been established using these drugs. This study aimed to compare the overall efficacy and safety of DPP-4is and the SGLT2i luseogliflozin in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM who had not used antidiabetic agents or who had used antidiabetic agents other than SGLT2is and DPP-4is were enrolled in the study after written informed consent had been obtained. The enrolled patients were subsequently randomly assigned to either the luseogliflozin or DPP-4i group and followed up for 52 weeks. The primary (composite) endpoint was the proportion of patients who showed improvement in ≥ 3 endpoints among the following five endpoints from baseline to week 52: glycated hemoglobin (HbA1c), weight, estimated glomerular filtration rate (eGFR), systolic blood pressure, and pulse rate. RESULTS: A total of 623 patients were enrolled in the study and subsequently randomized to either the luseogliflozin or DPP-4i groups. The proportion of patients who showed improvement in ≥ 3 endpoints at week 52 was significantly higher in the luseogliflozin group (58.9%) than in the DPP-4i group (35.0%) (p < 0.001). When stratified by body mass index (BMI) (< 25 or ≥ 25 kg/m2) or age (< 65 or ≥ 65 years), regardless of BMI or age, the proportion of patients who achieved the composite endpoint was significantly higher in the luseogliflozin group than in the DPP-4i group. Hepatic function and high-density lipoprotein-cholesterol were also significantly improved in the luseogliflozin group compared with the DPP-4i group. The frequency of non-serious/serious adverse events did not differ between the groups. CONCLUSION: This study showed the overall efficacy of luseogliflozin compared with DPP-4is over the mid/long term, regardless of BMI or age. The results suggest the importance of assessing multiple aspects regarding the effects of diabetes management. TRIAL REGISTRATION NUMBER: jRCTs031180241.

Thirty-year simulation of environmental fate of 137Cs in the Abukuma River basin considering the characteristics of 137Cs behavior in land uses.

The Fukushima Daiichi Nuclear Power Plant accident caused a radioactive contamination of deposited radionuclides, including 137Cs, on the land surface. Cesium-137 deposited on the land surface was strongly adsorbed on soil particles and was then washed off through soil erosion. Trends of temporal variation of 137Cs wash-off varied greatly depending on land use. Therefore, it is important to reflect the characteristics of 137Cs migration processes in each land use to clarify the long-term fate of 137Cs. In this study, a 30-year simulation of environmental fate of 137Cs was conducted using a distributed radiocesium prediction model, taking into account the characteristics of the 137Cs behavior in each land use. Overall, in the Abukuma River basin, the 137Cs transported into the ocean for 30 years was estimated to correspond to 4.6 % of the initial deposition in the basin, and the effective half-life of 137Cs deposited in the basin was estimated to be 3.7 years shorter (by 11.6 %) than its physical half-life. These results suggested that 137Cs deposited from the accident could still remain for decades. Based on the analysis of the 137Cs behavior in land use, in 2011, the contribution of 137Cs export to the ocean from urban lands was estimated to correspond to 70 % of the total 137Cs export. Meanwhile, from 2012 to 2040, the contribution of 137Cs export from agricultural lands was estimated to correspond to 75 % of the total 137Cs export. The reduction ratios excluding radioactive decay of 137Cs remained in areas with and without human activities for 30 years after the accident, defined as the ratios of the total outflow to the initial deposition, were estimated to be 11.5 %-17.7 % and 0.4 %-1.4 %, respectively. These results suggested that human activities enhance the reduction of 137Cs remaining in land in the past and future.

Relationships between cognitive appraisal and roles/personality traits in basic life support.

Objective: To examine the relationship between the cognitive assessment of stress (cognitive appraisal) caused in a scenario requiring basic life support (BLS) and the roles during BLS/personality traits in nursing students. Methods: We conducted an anonymous self-administered questionnaire survey for 264 freshman and senior nursing students. The study period was one month from June 2019. The questionnaire included characteristics, roles (active involvement group/passive involvement group/no involvement group), Cognitive Appraisal Rating Scale (CARS), and Maudsley Personality Inventory (MPI). We only included data for female students (107 people) in the analysis because very little data is available for male students. The Mann-Whitney test was used for the comparison between two groups and the Kruskal-Wallis test was used for the comparison between three groups. The significance level was set at p<0.05. Results: The total number of responses was 133 (50.4%), and the number of valid responses was 107 (40.5%). As a result of analyzing the relationship between the role and the CARS subscale, the controllability of the active and passive involvement groups was significantly lower than that of the no involvement group (p=0.046). Also, the analysis of the relationship between the grade and the CARS subscale showed that the controllability was significantly lower in freshmen than seniors (p=0.020). Conclusion: This study showed the relationship between controllability and cognitive appraisal of stress in the simulation scenario of BLS. Therefore, it was suggested that support for improving controllability is necessary as a preventive measure to reduce the stress associated with BLS.

Plasma Heparin Cofactor II Activity Is Inversely Associated with Hepatic Fibrosis of Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus.

AIMS: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs), and thrombin-induced activation of PARs promotes the development of non-alcoholic fatty liver disease (NAFLD). Since heparin cofactor II (HCII) specifically inactivates thrombin action, we hypothesized that plasma HCII activity correlates with the severity of NAFLD. METHODS: A cross-sectional study was conducted. Plasma HCII activity and noninvasive clinical markers of hepatic fibrosis including fibrosis-4 (FIB-4) index, NAFLD fibrosis score (NFS) and aspartate aminotransferase-to-platelet ratio index (APRI) were determined in 305 Japanese patients with type 2 diabetes mellitus (T2DM). The relationships between plasma HCII activity and the clinical markers were statistically evaluated. RESULTS: Multiple regression analysis including confounding factors showed that plasma HCII activity independently contributed to decreases in FIB-4 index (p＜0.001), NFS (p＜0.001) and APRI (p=0.004). In addition, logistic regression analysis for the prevalence of advanced hepatic fibrosis defined by the cutoff points of the clinical scores showed that plasma HCII activity was the sole and common negative factor for prevalence of advanced hepatic fibrosis (FIB-4 index: p=0.002, NFS: p=0.026 and APRI: p=0.012). CONCLUSIONS: Plasma HCII activity was inversely associated with clinical hepatic fibrosis indices including FIB-4 index, NFS and APRI and with the prevalence of advanced hepatic fibrosis in patients with T2DM. The results suggest that HCII can serve as a novel biomarker for assessment of hepatic fibrosis of NAFLD in patients with T2DM.

Safety and efficacy of filgotinib for Japanese patients with RA and inadequate response to MTX: FINCH 1 52-week results and FINCH 4 48-week results.

OBJECTIVES: To present safety and efficacy of the JAK1 preferential inhibitor filgotinib in Japanese patients with prior inadequate response (IR) to methotrexate (MTX) from a 52-week randomised controlled parent study (PS) and long-term extension (LTE) through June 2020. METHODS: The PS (NCT02889796) randomised MTX-IR patients to filgotinib 200 (FIL200) or 100 mg (FIL100), adalimumab (ADA) 40 mg, or placebo; all took stable background MTX. At week (W) 24, placebo patients were rerandomised to FIL200 or FIL100. The primary endpoint was W12 American College of Rheumatology 20% improvement; safety was assessed by adverse event (AE) reporting. For the LTE (NCT03025308), eligible filgotinib patients continued FIL200/FIL100; ADA patients were rerandomised (blinded) to FIL200 or FIL100; all continued MTX. RESULTS: In all, 114/147 Japanese patients completed the PS, 115 enrolled in LTE, and 103 remained on study in June 2020. In the PS, AEs were consistent with the overall population, and W24 efficacy was maintained or improved through W52, comparable with the overall population. LTE AE incidences were similar between doses; filgotinib efficacy was consistent from baseline to W48 and similar between PS ADA and filgotinib patients. CONCLUSIONS: Among MTX-IR Japanese patients, filgotinib maintained efficacy over 1 year; LTE safety was consistent with the PS.

Efficacy and safety of filgotinib as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a post-hoc analysis of the phase 2b/3 SELECTION trial.

BACKGROUND/AIMS: The safety and efficacy of filgotinib, a once-daily oral Janus kinase 1 preferential inhibitor, were evaluated in Japanese patients with ulcerative colitis (UC) in the phase 2b/3 SELECTION trial. METHODS: SELECTION (NCT02914522) was a randomized, placebo-controlled trial comprising 2 induction studies and a maintenance study. Adults with moderately to severely active UC were randomized in induction study A (biologic-naïve) or B (biologic-experienced) to receive filgotinib 200 mg, 100 mg, or placebo once daily for 11 weeks. Patients in clinical remission or Mayo Clinic score response at week 10 entered the 47-week maintenance study. Efficacy and safety outcomes were assessed in Japanese patients enrolled in Japan. RESULTS: Overall, 37 and 72 Japanese patients were enrolled in Japan in induction studies A and B, respectively, and 54 entered the maintenance study. Numerically higher proportions of filgotinib 200 mg-treated than placebo-treated patients achieved clinical remission in induction study A (4/15 [26.7%] vs. 0/6 [0%]) and the maintenance study (5/20 [25.0%] vs. 0/9 [0%]), but not induction study B (1/29 [3.4%] vs. 1/14 [7.1%]). Both doses were well tolerated, and no new safety signals were noted. Herpes zoster was reported in 1 filgotinib 200 mg-treated patient in each of induction study A (2.3%, 1/44) and the maintenance study (5.0%, 1/20). CONCLUSIONS: These data, alongside those of the overall SELECTION population, suggest the potential of filgotinib 200 mg as a viable treatment option for Japanese patients with UC. Owing to small patient numbers, data should be interpreted cautiously.

Integrated safety analysis of filgotinib treatment for rheumatoid arthritis in patients from Japan over a median of 1.5 years.

OBJECTIVE: Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA). METHODS: Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest. RESULTS: Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE). CONCLUSION: Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA.

Long-term safety and efficacy of filgotinib treatment for rheumatoid arthritis in Japanese patients naïve to MTX treatment (FINCH 3).

OBJECTIVES: To evaluate the long-term safety and efficacy of filgotinib (FIL) for Japanese patients with rheumatoid arthritis (RA) and limited/no prior methotrexate (MTX) exposure. We present a Japanese population subanalysis of a global randomised-controlled trial at Week 52 and interim long-term extension (LTE) to Week 48 through June 2020. METHODS: Patients were randomised to FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, or MTX for 52 weeks. At completion, eligible patients could enrol in the LTE. Those receiving FIL continued; those receiving MTX were rerandomised (blinded) to FIL 200 or 100 mg upon discontinuation of MTX. After a 4-week washout period, MTX could be re-added. RESULTS: Adverse event rates at Week 52 and in the LTE to Week 48 were comparable across treatment groups. Week 52 American College of Rheumatology 20% improvement (ACR20) rates were 83% (19/23), 82% (9/11), 75% (9/12), and 76% (19/25) for FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, and MTX, respectively. Through LTE Week 48, ACR20 rates were maintained. CONCLUSIONS: In the 56 Japanese patients treated with FIL, efficacy was maintained through Week 52 and beyond, with no increases in the incidence of adverse events.

Clinical Evaluation of Conventional Human Coronavirus Infection in Adults.

Human coronaviruses (HCoVs) are distributed globally and they cause a range of respiratory symptoms. Since HCoV infection usually causes mild upper respiratory tract disease and currently has no specific therapy, there are limited reports on its features, especially in adults. We aimed to evaluate the features of HCoV infections in clinical settings. Adult patients with respiratory symptoms from October 2014 to September 2019 at Nagasaki Genbaku Isahaya Hospital were enrolled. Multiplex reverse transcription-polymerase chain reaction as performed for 15 viruses, including HCoVs, and eight bacterial species on the patients' respiratory specimens. A total of 121 cases were recruited with HKU1, OC43, 229E, and NL63 strains in 80, 21, 12, and 11 cases, respectively. The percentage of HCoV-infected patients peaked in winter (47.5%). Symptoms of fever (69.4%), cough (47.9%), and comorbidities of asthma/cough variant asthma (34.7%) were frequently observed. Lymphocytopenia and increased C-reactive protein levels were observed in laboratory tests. Co-infection with other viruses was identified in 38.8% of the cases. In the repeat-positive cases, 42% were repeat positive within 100 days. HCoV-infected patients showed winter seasonality with a high frequency of comorbidity with asthma and co-infections. Re-infection within an early period was suspected, but further consideration is required.

Segmental Arteries and Veins at Higher Lumbar Levels Can Intersect the Adjacent Caudal Intervertebral Disc in the Anterior Part of the Spinal Column: A Cadaveric Analysis.

STUDY DESIGN: A cadaveric study. PURPOSE: To investigate the anatomical features of segmental arteries and veins in the anterior part of the spinal column to prevent segmental vessel injury. OVERVIEW OF LITERATURE: The lateral transpsoas approach to the lumbar intervertebral discs (IVD) is associated with the risk of segmental vessel injury. Previous studies have described the vascular anatomy on the lateral part of the vertebral body. However, there are no studies that describe the segmental vessels on its anterior aspect. Here, we report the important anatomical features of the segmental arteries and veins that can intersect the anterior part of the IVD. These vessels are considered at risk of vascular injury when placing the anterior retractors during lateral lumbar interbody fusion or cutting the anterior longitudinal ligament during anterior column realignment. METHODS: Five formalin-embalmed human cadavers were used. We assessed the proportion of segmental arteries and veins that intersected the IVD in the L2-L5 range and their course on the anterior part of the spinal column. RESULTS: The segmental arteries and veins commonly intersect the anterior part of the IVD (artery, 28.1%; vein, 42.1%). Seven of 10 (70%) segmental arteries at L2 intersected the IVD, but only one artery intersected the IVD at L3 and L4. The proportions of segmental veins that intersected the IVD were 60%, 50%, and 16.7% at L2, L3, and L4, respectively. CONCLUSIONS: The segmental arteries and veins frequently intersect the IVD in the anterior part of the spinal column. Therefore, it is necessary to consider these individual anatomical features to prevent vascular damage during lateral lumbar interbody fusion surgery.

Efficacy and safety of filgotinib in Japanese patients with refractory rheumatoid arthritis: Subgroup analyses of a global phase 3 study (FINCH 2).

OBJECTIVES: To evaluate efficacy and safety of filgotinib in Japanese RA patients who have failed or were intolerant to one or more biologic disease-modifying antirheumatic drugs (bDMARD) from the global FINCH 2 study (NCT02873936). METHODS: This subgroup analysis was performed using the predefined statistical analyses. The FINCH 2 study is a randomized, double-blind, placebo-controlled, Phase 3 study in adult RA patients with inadequate response to bDMARDs. The randomized patients were treated with once-daily filgotinib 200 mg, filgotinib 100 mg or placebo on a background of csDMARDs for 24 weeks. RESULTS: Of 449 patients enrolled in the overall population, 40 patients were enrolled from Japan. In the Japanese population, the American College of Rheumatology 20% response rates at week 12 (primary endpoint) were 83.3% and 53.3% for filgotinib, 200 mg and 100 mg, respectively, vs 30.8% for placebo. Filgotinib was well tolerated, similar to the overall population. CONCLUSIONS: Both doses of once-daily filgotinib 200 mg and filgotinib 100 mg were effective, and generally well-tolerated in Japanese patients with active refractory RA.

Efficacy and safety of filgotinib in combination with methotrexate in Japanese patients with active rheumatoid arthritis who have an inadequate response to methotrexate: Subpopulation analyses of 24-week data of a global phase 3 study (FINCH 1).

OBJECTIVES: Evaluate the efficacy and safety of the Janus kinase-1 inhibitor filgotinib in Japanese patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX). METHODS: Data from 147 Japanese patients in FINCH 1, a 52-week global Phase 3 study, were analysed up to 24 weeks. Patients received once-daily filgotinib 200 or 100 mg, biweekly adalimumab, or placebo, all with stable background MTX. RESULTS: In the Japanese population, American College of Rheumatology 20% response rates at Week 12 (primary endpoint) were 77.5%, 65.9%, 53.6%, and 36.8% for filgotinib 200 mg, filgotinib 100 mg, adalimumab, and placebo. Proportions of patients achieving Disease Activity Score with 28 joints <2.6 at Week 24: filgotinib 200 mg, 65.0%; filgotinib 100 mg, 51.2%; adalimumab, 42.9%; and placebo, 5.3%. Incidence rates of serious infections: filgotinib 200 mg, 2.5%; filgotinib 100 mg, 0%; adalimumab, 10.7%; and placebo, 5.3%. Treatment-emergent laboratory abnormalities Grade ≥3 occurred in five (12.5%) filgotinib 200 mg, three (7.3%) filgotinib 100 mg, one (3.6%) adalimumab, and no placebo patients. No deaths were reported among Japanese patients. CONCLUSIONS: Filgotinib once daily combined with MTX was effective and generally safe and well tolerated up to Week 24 in Japanese patients with RA and inadequate response to MTX.

Efficacy and safety of filgotinib alone and in combination with methotrexate in Japanese patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: Subpopulation analyses of 24-week data of a global phase 3 study (FINCH 3).

OBJECTIVES: To evaluate the efficacy and safety of filgotinib for Japanese patients with rheumatoid arthritis (RA) and limited or no prior methotrexate (MTX) exposure. METHODS: Data up to 24 weeks were analysed for 71 Japanese patients from a 52-week global Phase 3 study. Patients with RA and limited or no prior MTX exposure were randomised in a 2:1:1:2 ratio to filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, or MTX. Maximum MTX dose was 15 mg/week. Primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24. RESULTS: Week 24 ACR20 rates in Japanese patients were 82.6%, 90.9%, 83.3%, and 80.0% for filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, and MTX, respectively. Greater ACR20 rates with filgotinib vs MTX occurred at Week 2. Greater proportions receiving filgotinib vs MTX achieved DAS28-CRP <2.6 at Weeks 12 and 24. Adverse event rates were comparable across treatments and between the Japanese and overall populations. CONCLUSIONS: While Week 24 ACR20 rates were similar, filgotinib provided faster responses and higher remission rates vs MTX. In Japanese patients with RA and limited or no prior MTX exposure, filgotinib was generally well tolerated.

Measuring serum prothrombin in patients treated with warfarin or direct oral anticoagulants.

BACKGROUND: Warfarin therapy influences generation of γ-carboxyglutamyl (Gla) residues in prothrombin, causing reduced coagulation activity. It will leave such inactive prothrombin in serum after clot formation, resulting in serum prothrombin constituting total inactive prothrombin in these patients. METHODS: An ELISA was developed to measure biologically inactive prothrombin in serum, and applied to serum from warfarin therapy causing a decrease in Gla residues or direct oral anticoagulant (DOAC) therapy as its contrast. RESULTS: The concentrations of serum prothrombin in both the warfarin and DOAC groups were higher than those in the healthy group (p < 0.01 and p < 0.001, respectively). When serum in the previous three groups was treated with barium carbonate to exclude prothrombin, which lost several Gla residues, the prothrombin concentration in the DOAC group decreased to the same level as that in the healthy group, indicating that prothrombin was obtained at a high level only in the warfarin group (p < 0.01). CONCLUSIONS: Warfarin and DOAC led to increase in serum prothrombin concentration. The reason is that DOAC decreases prothrombin recruitment during fibrin clot formation, while warfarin leads to the accumulation of inactive prothrombin, which have a decreased number of Gla residues.

Clinical evaluation of QuantiFERON®-TB Gold Plus directly compared with QuantiFERON®-TB Gold In-Tube and T-Spot®.TB for active pulmonary tuberculosis in the elderly.

BACKGROUND: Reduced sensitivity of tuberculosis (TB) interferon-γ release assays (IGRAs) among the elderly has been reported, which is presumably due to diminished immune function. We evaluated the clinical performance of QuantiFERON®-TB Gold plus (QFT-Plus) compared with QuantiFERON®-TB Gold In-Tube (QFT-GIT) and T-Spot®.TB (T-SPOT) in the elderly. METHODS: Blood samples for all three IGRAs were drawn at the same time from all the participants. Both CD4 and CD8 T-cell counts in patients' peripheral blood were also measured. RESULTS: A total of 142 active pulmonary TB patients (median age: 84, interquartile range; 76-89 years) were recruited. The sensitivities of the tested IGRAs (excluding invalid/indeterminate cases) were as follows: QFT-Plus, 93.6%; QFT-GIT, 91.4%; and T-SPOT 68.1%. QFT-Plus displayed significantly higher sensitivity than T-SPOT (p < 0.00001). All three IGRAs exhibited the same specificity (100%), as assessed using blood samples from healthy, low TB-risk individuals (n = 118; median age: 39, IQR; 32-47 years). Positivity in 43 active TB patients with CD4 T-cell counts <200/µL, 39 of whom were ≥80 years of age, was as follows: QFT-Plus, 83.7%; QFT-GIT, 74.4%; and T-SPOT, 58.1%. The difference between TB2-TB1 of the QFT-Plus assay was statistically correlated with CD8 but not CD4 T-cell counts in blood (r = 0.193, p = 0.0298). CONCLUSIONS: QFT-Plus showed high performance in the detection of TB infection in patients irrespective of their advanced age (≥80 years) or lower CD4 counts. QFT-Plus can be useful for the diagnosis of TB infection in all patients, including those who are elderly and/or immunocompromised.

Plasma heparin cofactor II activity is inversely associated with albuminuria and its annual deterioration in patients with diabetes.

AIMS/INTRODUCTION: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria. MATERIALS AND METHODS: Plasma HCII activity and spot urine biomarkers, including albumin and liver-type fatty acid-binding protein (L-FABP), were determined as the urine albumin-to-creatinine ratio (uACR) and the urine L-FABP-to-creatinine ratio (uL-FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females). RESULTS: The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate-regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log-transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL-FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log-transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively). CONCLUSIONS: The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria.

Tunable vacuum ultraviolet cross-luminescence from KMgF under high pressure as potential fast-response scintillator.

We report on the potential of the potassium magnesium fluoride (KMgF) crystal as a fast-response scintillator with tunable cross-luminescence (CL) emission wavelength through high-pressure applications. By performing first-principles density functional theory calculations using the Perdew-Burke-Ernzerhof (PBE) hybrid functional including exact exchange (PBE0) and Green's function and screened Coulomb interaction approximation as implemented in the Vienna Ab initio Simulation Package using plane-wave basis sets within the projector-augmented wave method, we identify the specific valence-to-core band transition that results in the experimentally observed CL emission at 148 nm (8.38 eV) and 170 nm (7.29 eV) wavelengths with intrinsically fast decay times of 290 ps and 210 ps, respectively. Uniform volume compression through hydrostatic high-pressure applications could decrease the energy gap between the valence and core bands, potentially shifting the CL emission wavelength to the ultraviolet (UV) region from 200 nm (6.2 eV) to 300 nm (4.1 eV). The ability to tune and shift the CL emission to UV wavelengths allows for the detection of the CL emission using UV-sensitive photodetectors in ambient atmosphere instead of highly specialized vacuum UV detectors operating in vacuum while maintaining the intrinsically fast CL decay times, thereby opening up new possibilities for KMgF as a fast-response scintillator.