T he glymphatic system, which is a glial-dependent waste clearance pathway, is an emerging circulatory model in the brain and is characteristically devoid of authentic lymphatic vessels (1). The key component of the glymphatic system is the perivascular space. At the periarterial space, cerebrospinal fluid (CSF) enters the interstitial space of the brain through the aquaporin-4 water channels at the end feet of astrocytes (2). CSF mixed with interstitial fluid then exits the brain via the perivenous space along with metabolic waste products. The waste clearance pathway downstream to the glymphatic system comprises meningeal lymphatic vessels, an authentic lymphatic network found at the dura, cranial nerves, and large vessels at the skull exits (3).Accumulating evidence suggests the clearance of metabolites, such as t protein, amyloid-b, and lactate from the brain through the glymphatic system (2,4,5). Impairment of the glymphatic system is an important pathophysiology of various abnormal conditions, including Background: Evaluation of the glymphatic system with intrathecal contrast material injection has limited clinical use. Purpose:To investigate the feasibility of using serial intravenous contrast-enhanced T1 mapping in the quantitative evaluation of putative dynamic glymphatic activity in various brain regions and to demonstrate the effect of sleep on glymphatic activity in humans. Materials and Methods:In this prospective study from May 2019 to February 2020, 25 healthy participants (mean age, 25 years 6 2 [standard deviation]; 15 men) underwent two cycles of MRI (day and night cycles). For each cycle, T1 maps were acquired at baseline and 0.5, 1, 1.5, 2, and 12 hours after intravenous contrast material injection. For the night cycle, participants had a normal night of sleep between 2 and 12 hours. The time (t min ) to reach the minimum T1 value (T1 min ), the absolute difference between baseline T1 and T1 min (peak DT1), and the slope between two measurements at 2 and 12 hours (slope [2h-12h] ) were determined from T1 value-time curves in cerebral gray matter (GM), cerebral white matter (WM), cerebellar GM, cerebellar WM, and putamen. Mixed-model analysis of variance (ANOVA), Friedman test, and repeated-measures ANOVA were used to assess the effect of sleep on slope (2h-12h) and to compare t min and peak DT1 among different regions. Results:The slope (2h-12h) increased from the day to night cycles in cerebral GM, cerebellar GM, and putamen (geometric mean ratio [night/day]

Funding information Takeda Pharmaceutical Company[Correction added on 2 July 2021, after first online publication: the ClinicalTrials.gov number in the Methods-Study subject section has been corrected from "NCT02802735" to "NCT02892409" in this current version.] Aims: Helicobacter pylori (Hp) eradication plays a key role in the treatment and prevention of peptic ulcer diseases. Increasing clarithromycin resistance in Hp necessitates more effective treatments for eradication, such as bismuth-containing quadruple therapy. We aimed to compare the safety and pharmacokinetics (PK) of bismuth between vonoprazan-and lansoprazole-containing quadruple therapy in Hppositive subjects.Methods: In this randomised, double-blind, parallel-group study, Hp-positive subjects were randomised to receive vonoprazan-or lansoprazole-containing quadruple therapy. Each subject received vonoprazan 20 mg or lansoprazole 30 mg combined with bismuth 220 mg, clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 14 days. Blood sampling and urine collection for bismuth PK were conducted predose and up to 12 hours postdose at steady-state. The PK parameters of bismuth were derived using a noncompartmental method and compared between treatments.An exploratory breath test for Hp was conducted at screening and at the follow-up visit on day 42. Safety was assessed by adverse event monitoring, physical examinations, vital signs, 12-lead electrocardiograms and clinical laboratory tests.Results: A total of 30 subjects were randomised and 26 subjects completed the study (12 in the vonoprazan group and 14 in the lansoprazole group). The systemic exposure of bismuth in the 2 treatments was comparable (5% difference). All subjects turned negative for Hp at the follow-up visit. No significant difference in safety profiles was noted between the 2 treatments. Conclusion:The systemic exposure of bismuth was similar between vonoprazan-and lansoprazole-containing quadruple therapy. Vonoprazan-containing quadruple therapy was safe and well tolerated.

Blockchain is a novel data architecture characterized by a chronological sequence of blocks in a decentralized manner. We aimed to evaluate the real-world feasibility of a blockchain-based dynamic consent platform (METORY) in a decentralized and multicenter trial. The study consisted of three visits (i.e., screening and

Aims We performed a first‐in‐human study with HL2351, a novel hybrid Fc‐fused interleukin (IL)‐1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. Methods A randomized, double‐blind, placebo‐ and active‐controlled, dose‐escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active‐controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex‐vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL‐1β. Anti‐HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. Results HL2351 was eliminated more slowly than anakinra (terminal half‐life: 27.21–45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose‐proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL‐6 expression varied widely (range: 0–92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. Conclusion HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7‐11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

Objectives: Digital therapeutics (DTx) are software-based therapeutic interventions based on clinical evidence. Randomized clinical trials (RCTs) are often the source of clinical evidence, similar to conventional drugs or medical devices. However, novel approaches such as the use of real-world data or digital biomarkers are also utilized. This article aimed to review how DTx products have been clinically evaluated. Methods: DTx products approved by the US Food and Drug Administration as of 2020 were reviewed and products with sufficient published information were selected. Pivotal clinical trials were analyzed according to the elements of the Consolidated Standards of Reporting Trials (CONSORT) guideline. Case reviews were presented for other clinical evaluation strategies, considering the small number of publications. Results: Most approved DTx products used RCTs for clinical evaluations. Similar to conventional RCTs, parallel-group designs with statistical hypothesis testing were adopted. However, DTx trials were often not blinded due to practical issues and involved various comparator groups. In addition, DTx products could be readily evaluated in home-based settings and delivered through the internet. Other evaluation approaches included retrospective analyses using insurance claims data or usage data, which enabled long-term evaluations of effectiveness. Digital biomarkers obtained from real-time and continuous log data were also used to improve the objectiveness of endpoints. Conclusions: RCTs accounted for the majority of DTx evaluations. The designs of DTx trials were comparable to those of drug or device trials, but blinding and comparator elements were often different. Furthermore, the use of real-world data and digital biomarkers are also being tried.