Kitasato Institute Hospital

Background/Objectives: This study aimed to describe the population pharmacokinetics of cefazolin (CFZ) using unbound serum and periprostatic adipose tissue concentrations and to optimize dosing regimens for patients undergoing robotic-assisted radical prostatectomy (RARP). Methods: We investigated the population pharmacokinetics of CFZ using 295 unbound serum and 67 periprostatic adipose tissue samples from 67 individuals. CFZ concentrations were determined in all samples. A nonlinear mixed-effects model was developed. The pharmacodynamic target was defined as maintaining unbound trough and periprostatic adipose tissue concentrations exceeding the minimum inhibitory concentration (MIC) against methicillin-susceptible Staphylococcus aureus (MSSA) for over 90% of the dosing interval (MIC90; 0.5 mg/L). Results: Systemic clearance of unbound CFZ was significantly associated with creatinine clearance (CLcr). In patients with normal renal function, simulations showed that a 1 g CFZ infusion over 15 min maintained unbound concentrations exceeding the MSSA MIC90 for >90% of the 3 h interval after the initial dose. Notably, in patients with mild renal impairment (CLcr ≤ 80 mL/min), a 5 h dosing interval also achieved a >90% probability of maintaining the target CFZ concentration. Conclusions: The simulations demonstrated that the probability of target attainment of >90% was maintained for up to 5 h in patients with mild renal impairment (CLcr ≤ 80 mL/min). These findings provide a pharmacokinetic rationale suggesting that the standard additional dose may not be necessary for this subgroup; however, future clinical studies are needed to validate safety and efficacy.

INTRODUCTION:Anti-integrin αvβ6 (anti-αvβ6) autoantibodies serve as a diagnostic biomarker and are associated with poor prognosis in ulcerative colitis (UC). We aimed to investigate whether anti-αvβ6 autoantibody levels predict treatment outcomes of advanced therapies in patients with moderately to severely active UC.METHODS:Anti-αvβ6 autoantibody levels were measured using prospectively collected serum samples at the initiation of advanced therapies. The primary outcome was treatment persistence up to 1 year; secondary outcomes included clinical remission rates at weeks 2, 6, 14, 24, and 48, comparing low-level and high-level groups stratified by an optimal cutoff from receiver operating characteristic analysis.RESULTS:A total of 144 patients were analyzed (121 [84.0%] with extensive colitis and 87 [60.4%] with prior exposure to advanced therapies). The median observation period was 10 months, and treatment discontinuation occurred in 70 patients (48.6%). Treatment persistence was significantly higher in the low-level group (log-rank test, P = 0.002), and multivariable Cox analysis identified low antibody levels as the only independent predictor (hazard ratio, 1.90; 95% CI, 1.09–3.32). Clinical remission rates were consistently higher in the low-level group throughout all time points, with the greatest difference at week 6 (47.5% vs 20.0%; χ2 test, P = 0.003). Low antibody levels remained an independent predictor of remission at all time points.DISCUSSION:Anti-αvβ6 autoantibodies predicted both treatment persistence and clinical remission after advanced therapies, highlighting their potential as a predictive biomarker in patients with active UC.

We investigated the impact of operating room pharmacists on the appropriate use of antimicrobial prophylaxis (AMP) in otorhinolaryngology-head and neck surgery. Patients without intervention by operating room pharmacists (April 1, 2017, to March 31, 2019) and those who underwent intervention by operating room pharmacists (October 1, 2019, to March 31, 2021) were compared. Additionally, an interrupted time-series (ITS) analysis was conducted as a sensitivity analysis to assess temporal trends. Overall, 1697 patients (999 in the non-intervention group and 698 in the intervention group) were included, and 213 matched pairs were analyzed after 1 : 1 propensity score matching. The compliance rate of AMP administered within 1 h prior to incision was significantly higher in the intervention group than in the non-intervention group (98.1 vs. 93.4%; p = 0.027). In the subgroup analysis, the compliance rate of the guideline-recommended initial dose in patients weighing ≥80 kg was significantly higher in the intervention group than in the non-intervention group (93.1 vs. 70.7%; p < 0.001). The compliance rate of additional doses administered at the guideline-recommended intervals in patients with an estimated glomerular filtration rate individualized body surface area (eGFRind) <50 mL/min was significantly higher in the intervention group than in the non-intervention group (89.8 vs. 80.4%; p = 0.041). ITS analysis showed that the improvement trend in AMP compliance stabilized after the intervention, indicating sustained intraoperative management. No significant differences were observed in the postoperative or total hospital stay between the two groups. In conclusion, interventions by operating room pharmacists significantly improved the appropriate use of intraoperative AMP.

Background/Objectives: Although vonoprazan-based triple therapy has improved the first- and second-line Helicobacter pylori eradication rates, a subset of patients still require third-line or later treatments. The present study aimed to evaluate the efficacy and safety of susceptibility-guided eradication strategies from third-line or later treatments in a multicenter setting. Methods: This retrospective multicenter study (2019-2024) enrolled 94 patients who had failed second-line eradication therapy and underwent H. pylori isolation and susceptibility testing. Based on sitafloxacin sensitivity, patients received vonoprazan, amoxicillin, and sitafloxacin (VAS) if sensitive, or vonoprazan, amoxicillin, and rifabutin (VAR) if resistant. Altogether, 75 patients received treatment according to this protocol. Results: Among the 75 patients, 61.3% were sitafloxacin-sensitive (VAS group), and 38.7% were resistant (VAR group). All strains were rifabutin-sensitive. The overall eradication rates were 92.0% and 95.8% in the intention-to-treat and per-protocol analyses, respectively. Adverse events occurred in 17.3% of cases. One patient in the VAR group discontinued therapy due to dizziness, whereas all other adverse events were mild and did not require treatment cessation. Subgroup analysis showed eradication rates of 93.5% (43/46) and 89.7% (26/29) for the VAS and VAR groups, respectively. The eradication rate for third-line therapy was 96.2% (50/52), whereas that for fourth-line therapy was 85.7% (18/21). Fifth-line therapy showed an eradication rate of 50.0% (1/2). Conclusions: Susceptibility-guided vonoprazan-based regimens from the third-line treatment onward achieved high eradication and tolerability in a multicenter cohort. This approach may offer a valuable treatment option for patients with refractory H. pylori infections.

Abstract Background Mirikizumab (MIRI), a p19-directed interleukin-23 monoclonal antibody, has demonstrated efficacy and safety through Week (W)212 in moderately-to-severely active ulcerative colitis (UC; LUCENT-1: W0-W12, NCT03518086; LUCENT-2: W12-W52, NCT03524092; LUCENT-3: W52-W212, NCT03519945).1 Preventing UC-related hospitalisations and surgeries is a SPIRIT consensus goal to achieve in disease-modification trials.2 Lower rates of UC-related hospitalisations and surgeries were observed in patients treated with MIRI compared to those treated with placebo (PBO) during LUCENT-1, and that impact continued through LUCENT-2 with no UC-related hospitalisations or surgeries reported in MIRI-treated patients.3 We assessed rates of UC-related hospitalizations and surgeries through W212. Methods In LUCENT-1 (induction), patients were randomized to intravenous MIRI 300mg (N = 868) or PBO (N = 294) every 4 weeks (Q4W) for 12W. Patients randomized to MIRI induction and achieving clinical response at W12 were re-randomized 2:1 in LUCENT-2 (maintenance) to subcutaneous (SC) MIRI 200mg Q4W (N = 365) or PBO (N = 179) for maintenance; 316 of the MIRI-treated patients entered the open-label extension LUCENT-3 and continued receiving SC MIRI 200 mg Q4W for 160W (W212 of continuous treatment). Hospitalisations linked to an adverse event with a stay of ≥ 24 hours were recorded. Only UC-related hospitalisations were used for analysis. UC-related surgery was defined as total colectomy, partial colectomy, and proctocolectomy. Proportions and exposure-adjusted incidence rates (IRs) of UC-related hospitalisation and UC-related surgery were analysed from the 3-year LUCENT-3 study among MIRI-treated patients. Results During LUCENT-3, total exposure among the 316 patients was 835 patient-years. Proportions and IRs for each year of the 3-year LUCENT-3 study are shown in Table 1. There was one UC-related hospitalisation due to exacerbation of UC and no UC-related surgeries observed in MIRI-treated patients (IRs 0.1 and 0 per 100 patient-years, respectively). The reduction in UC-related hospitalisations and surgeries among MIRI-treated patients was maintained through LUCENT-2 and continued in LUCENT-3 (Figure 1). Conclusion MIRI reduced UC-related hospitalisations and surgeries which were maintained through 4 years of treatment, demonstrating MIRI’s disease modifying potential and sustained long-term maintenance of efficacy, a key element of comprehensive disease control.

The patient was a 56-year-old woman who had previously undergone living-donor kidney transplantation, followed by urinary diversion surgery due to recurrent pyelonephritis. Nine years after the urinary diversion, abdominal computed tomography performed for evaluation of lower abdominal pain revealed a renal calculus in the transplanted kidney. Percutaneous nephrolithotomy resulted in satisfactory stone fragmentation, but had to be performed again 14 months later to remove a residual stone that had increased in size.

Studies on the association between chest computed tomography (CT) findings of extensive pulmonary involvement and long-term pulmonary and extrapulmonary coronavirus disease 2019 (COVID-19) sequelae are lacking. This study aimed to investigate the relationship between the severity of pneumonia on admission and residual pulmonary and extrapulmonary complications at three months post-hospitalization. Using data from the Japan COVID-19 Task Force database, we conducted quantitative analysis of CT scans of 164 patients obtained at admission and three months later. The parameters included pneumonia volume, total lung volume, and area and density of the pectoralis muscle (PM), subcutaneous and epicardial adipose tissue, and vertebral bone density. Patients with extensive pneumonia on admission had high residual pneumonia volumes, reduced lung volumes, and decreased area and density of PM at three months. No significant differences were observed in the adipose tissue or bone parameters. The severity of pneumonia at admission was independently associated with PM atrophy. CT-based quantification of pneumonia extent during the acute phase of COVID-19 may be useful in predicting long-term pulmonary sequelae and muscle wasting. This approach may allow the objective evaluation of Long COVID and facilitate the identification of potential therapeutic targets.

Abstract AimSchizophrenia spectrum disorders are among the most serious mental illnesses that cause social dysfunction. Patients with schizophrenia spectrum disorders are prone to recurrence, and those who require hospitalization are at a high risk; hence, preventing treatment failure after discharge is essential. Therefore, we conducted a retrospective study to identify the factors associated with treatment failure after discharge in patients with schizophrenia spectrum disorders who received psychiatric inpatient treatment.MethodsThis study included 859 patients diagnosed with schizophrenia spectrum and other psychotic disorders who were hospitalized at the Department of Psychiatry in Kitasato University Hospital and Kitasato University East Hospital from January 1, 2014, to December 31, 2021. Treatment failure was defined as discontinuation of outpatient care, psychiatric hospitalization, or death within 1 year after discharge.ResultsOf the 859 patients, 201 (23.4%) experienced treatment failure. Treatment failure rate was 29.0% in patients undergoing antipsychotic polypharmacy, significantly higher than that in patients who were not. Additionally, treatment failure was 20.8% in patients who had a trial overnight stay at home during hospitalization, significantly lower than that in patients who did not.ConclusionAntipsychotic polypharmacy at discharge was associated with treatment failure in patients with schizophrenia spectrum disorders. Additionally, trial overnight stays at home during hospitalization potentially contributed to preventing treatment failure. Therefore, preventing treatment failure in patients with schizophrenia spectrum disorder requires optimizing pharmacotherapy and implementing social and environmental adjustments, focusing on the post‐discharge period.

Background and AimsOzanimod is a once-daily, oral, selective sphingosine 1-phosphate receptor 1 and 5 modulator. The objective of the randomized, phase 2/3 J-True North study (NCT03915769) was to assess the efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis.MethodsIn the 12-week induction period (IP), patients were randomized 1:1:1 to receive placebo, ozanimod 0.46 mg, or ozanimod 0.92 mg. Patients who completed the IP with a clinical response at week (w) 12 were eligible to enter a 40-week maintenance period where they received the same treatment as they did in the IP. The primary endpoint was clinical response (complete Mayo score) at w12; clinical and mucosal secondary endpoints were assessed at w12 and w52.ResultsOf 198 patients randomized, 176 completed the IP. Of these patients, 97 entered and 77 completed the maintenance period. A significantly higher proportion of patients receiving ozanimod achieved clinical response at w12 versus placebo (ozanimod 0.46 mg: 52.9%, P = .0158; ozanimod 0.92 mg: 61.5%, P = .0006; vs placebo: 32.3%). Similar results were observed in the secondary endpoints where patients receiving ozanimod achieved higher rates of clinical remission, endoscopic improvement, and mucosal healing at w12 than those receiving placebo. Efficacy was maintained at w52 for all endpoints. Both doses of ozanimod were well tolerated, with no unexpected safety signals.ConclusionThis large-scale clinical trial demonstrated the efficacy and safety of once-daily oral ozanimod in Japanese patients with moderately to severely active ulcerative colitis. This is the first time that the efficacy and safety of ozanimod were verified in a large number of patients in Asia.

Background:Mucosal histological activity is increasingly valued as a treatment endpoint in inflammatory bowel diseases (IBD). In the Asia Pacific region, the utility and acceptability of IBD histology as a treatment endpoint are uncertain due to the heterogeneity of IBD prevalence, resourcing and level of knowledge among practitioners. There is an opportunity to engage clinicians to harmonise histology reporting and collaborate with pathologists in this field.Objectives:We aimed to develop consensus statements through anonymous voting on histological features, processing, reporting and relevance to treatment outcomes in IBD, including ulcerative colitis (UC) and Crohn’s disease (CD).Design:The consensus document was developed through a comprehensive literature review, followed by a deliberation process among experts in the field.Methods:Representatives of the Asia Pacific Association of Gastroenterology, in collaboration with pathologists, voted anonymously in accordance with modified Delphi methodology on statements relevant to IBD and histology. Domains of interest were histological features of UC and CD, relevance to clinical management and the potential utility of artificial intelligence (AI) in grading histological disease severity. Level of evidence and recommendation grade were included in accordance with the National Health and Medical Research Council, Australia guidelines of Australia.Results:Consensus was reached on 37 out of 38 statements concerning definitions, pathology processing and reporting, scoring system and relevance to clinical outcomes. Knowledge gaps were identified with uncertainty over the role of AI.Conclusion:These consensus statements provide recommendations, with specific relevance to the Asia Pacific region, on the role of histology in IBD to harmonise its use. The statements will promote understanding and applicability in research and in the routine management of IBD.