Shionogi (Japan)

This cross-sectional study explored outcomes in patients with cancer following opioid initiation (maximum observation period: 6 months), based on an analysis of laxative prescription patterns for opioid-induced constipation (OIC) using the Medical Data Vision Co., Ltd., a nationwide acute care hospital claims database in Japan. Of 26,939 patients included, 16,214 (60.2%) developed OIC, defined as the prescription of a laxative on or after the fourth day following the initiation of opioid therapy. At baseline, the average age was 69.3 years, with 58.0% being male patients. Overall, 42.7% of patients were hospitalized at the time of opioid initiation (OIC subgroup: 51.1%; non-OIC subgroup: 30.1%). The majority of patients (53.9%) had observation data for less than 6 months (OIC subgroup: 61.8%; non-OIC subgroup: 42.0%). Although there were disparities in patient backgrounds and observation periods, the total healthcare costs incurred were approximately ¥2,400,000, with ¥2,800,000 in the OIC subgroup and ¥1,800,000 in the non-OIC subgroup. Overall, these results highlight the importance of implementing appropriate OIC management strategies in Japan. However, it is noteworthy that the sequence of events between OIC onset and clinical outcomes remains unclear.

Major depressive disorder (MDD) shows varied treatment responses. Previous Phase 2 and 3 trials demonstrated the efficacy of 2-week oral zuranolone in Japanese MDD patients, but individual symptom trajectories were not analyzed. To address this gap, this study aimed to characterize patterns of depressive symptom trajectories among these patients. We conducted a pooled analysis of Phase 2/3 randomized, double-blind, placebo-controlled trials in Japanese adults with MDD. Participants received zuranolone 30 mg or placebo once daily for 14 days, with a 6-week follow-up. Patients with complete 17-item Hamilton Rating Scale for Depression (HAM-D17) data at baseline and 10 subsequent time points through Day 57 were included. Change from baseline scores underwent Dynamic Time Warping-based k-means clustering identified symptom trajectory patterns in the zuranolone group, with optimal cluster number determined by the elbow method. A Random Forest classifier then assessed scale items linked to symptom worsening trajectories. Four distinct trajectories were identified. Three clusters showed varying degrees of symptom reduction during treatment, stabilizing during follow-up. The fourth cluster showed symptom reduction during the treatment period and a mean increase in HAM-D17 scores after Day 15, primarily due to worsening insomnia. Each Patient Health Questionnaire-9 (PHQ-9) score showed a similar course to the corresponding HAM-D17 scores. No notable differences were observed among clusters in baseline demographics, episode duration, or initial severity. This study reveals diverse symptom trajectories in zuranolone-treated patients and provides clinically relevant insights, highlighting the importance of early post-dosing monitoring-particularly of sleep symptoms-to inform clinical management and future research.

The COVID-19 pandemic, spanning from early 2020 to late 2022, posed unprecedented challenges for global public health. However, it also spurred innovative approaches to pandemic management, notably the development of pathogen detection in wastewater. It was successfully demonstrated that wastewater analysis can not only reflect ongoing COVID-19 infections but also serve as an early indicator of disease prevalence within communities. Recognizing the value of longitudinal analyses of various pathogens, we identified the need for wastewater biobanking. This practice allows for the retrospective analysis of samples, offering critical public health insights at the population level. Moreover, the potential to transport and store biobanked samples at ambient temperature or in a dry state could greatly enhance the utility of this technology, especially in resource-limited settings such as low- and middle-income countries. This article also addresses the ethical considerations and public health implications of wastewater-based epidemiology. While this approach holds significant potential beyond pathogen detection, it is essential to evaluate the benefits and potential risks carefully.

The reference method for determining cefiderocol MIC is broth microdilution (BMD) using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB). However, laboratories have reported variable MIC findings and difficulties in determining MIC endpoints. To investigate this, the BMD method was re-evaluated by examining the chelation time for iron depletion of the media and by testing reproducibility using four MHB sources (BD-BBL, BD-Difco, Oxoid, and Merck) and 85 Gram-negative isolates (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii), of which 63 were previously evaluated in vivo. Extending chelation time to 6 h provided optimal iron reduction to ≤0.03 µg/mL for all media. MIC reproducibility was high for each medium source and varied by species (93.3%-99.0% of MIC values within one dilution of modal MIC values); however, different sources of ID-CAMHB produced (reproducible) different modal MIC values for isolates. ID-CAMHB from BD-BBL and BD-Difco showed the best correlation with 96.5% of isolates showing modal MIC values within one dilution between media. MIC values generated with these two media were the most predictive of efficacy in vivo. When trailing was observed, it was seen across all media, and refined reading guidelines were applied to enhance reproducibility of determining the MIC endpoint. The 6-h chelation and the refined reading guidelines for trailing are now incorporated into the Clinical and Laboratory Standards Institute M100 document. When using the BMD method to determine cefiderocol susceptibility, the impact of media should be considered, and based on these results, ID-CAMHB prepared with BD-BBL or BD-Difco is recommended.IMPORTANCEThe reference antibiotic susceptibility testing method for cefiderocol is the broth microdilution method approved by the Clinical and Laboratory Standards Institute in 2016, using iron-depleted cation-adjusted Mueller-Hinton broth. A few manual devices have come to the market replicating this method, but inconsistent results with these devices have been reported. The current study identified the source of Mueller-Hinton broth as a variable in cefiderocol MIC determinations and provides detailed description of the preparation of iron-depleted cation-adjusted Mueller-Hinton broth, and revised reading guidance to improve reproducibility of cefiderocol MIC determinations for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The recommendations made in this study should enhance the reproducibility of cefiderocol broth microdilution susceptibility testing.

The Rare Disease Consortium Japan (RDCJ) is a newly formalized cross-sector initiative launched to address the urgent and growing needs of individuals living with rare diseases in Japan, aiming to support a wide range of rare conditions, including—but not limited to—neuromuscular diseases. RDCJ hosted its inaugural symposium on July 18, 2023, at the Shonan Health Innovation Park. This symposium aimed to address the unique challenges of rare diseases through a collaborative approach involving industry, government, academia, patients, and the community. The event brought together these stakeholders to discuss the current state and future directions of rare disease research and treatment in Japan. The event featured a range of speakers and panel discussions on the state of drug development, patient journeys, and the future of patient-centered healthcare services. Highlights included a keynote on antisense oligonucleotide therapeutics and sessions on patient-centered healthcare, human-centered design in healthcare, and innovative approaches to rare disease treatment. This report provides a detailed overview of the symposium, the key takeaways from each session, and the future directions for RDCJ.

The plasma histidine-rich glycoprotein concentration is a marker of sepsis severity. In this study, we generated selective and specific monoclonal antibodies against histidine-rich glycoprotein for use in a prototype enzyme-linked immunosorbent assay-based in vitro diagnostic system. First, we investigated the properties of monoclonal antibodies produced by 21 hybridomas that we developed using immunized mice, and we identified monoclonal antibodies 69-1A and 75-2D to be the most suitable combination for use in the sandwich enzyme-linked immunosorbent assay. Wild-type histidine-rich glycoprotein (Form-1, 75kDa) with a proline residue at amino acid position 204 is the most common isoform of the protein in humans, followed by its variant (Form-2, 77kDa), which has a serine residue at position 204. The epitope mapping was examined for the HRG amino acid sequence with 69-1A and 75-2D mAbs to achieve the identification of respective specific binding domains, though the other kinds of mAbs showed considerably complex domains. The identified epitopes recognized by 69-1A and 75-2D monoclonal antibodies did not span position 204. Furthermore, immunoprecipitation-immunoblotting analysis showed that the 69-1A and 75-2D monoclonal antibodies could bind to both Form-1 and Form-2 in human plasma samples. Thus, these two new antibodies can be used to clearly detect both forms of histidine-rich glycoproteins in human plasma samples. In our analysis of clinical samples by enzyme-linked immunosorbent assays using various combinations of our newly synthesized antibodies, we found that the histidine-rich glycoprotein concentration was significantly lower in plasma samples from septic patients than in those from healthy volunteers (p<0.01). Thus, our novel analysis system using the new antibodies is expected to be a useful tool for sepsis research, and it may be adapted as an in vitro diagnostic tool for many other kinds of diseases in the future.

Coccidioidomycosis (CM) has been a recognized disease for about 130 years. The organisms (Coccidioides spp. fungi) inhabit desert soil in the southwestern USA, Mexico, and parts of Central and South America. Natural events such as dust storms, wildfires or outdoor activities including construction and gardening can disrupt the fungal arthroconidia, which easily become airborne and inhaled by the host. Approximately 60% of those exposed to arthroconidia are asymptomatic and do not require medical attention, but 30% show signs of pulmonary infection with symptoms ranging from a flu-like illness to pneumonia. In 5%-10% of cases serious or disseminated disease develops, which requires prompt diagnosis and management. About 1%-3% of infections disseminate to the CNS and if not appropriately treated are often fatal. There is an urgent need for improved diagnostics and treatments.

Abstract Malaria poses a significant health burden to endemic countries, necessitating the development of new antimalarials with novel mechanisms of action to combat emerging drug resistance. However, target identification methods for antimalarial compounds selected through phenotypic screening are currently limited, which has been a major obstacle in the field of antimalarial drug discovery. Here, we aim to address this need using perturbation transcriptomics to efficiently select antimalarial compounds targeting new pathways or molecules. The method involves comparing the transcriptomic changes by drug perturbation in the asexual blood stage of the malaria parasite Plasmodium falciparum. Using this method, we identified several compounds that exhibited distinct transcriptomic profiling from a diverse set of antimalarials with known modes of action, indicating their potential to target different pathways. In addition, we successfully identified a novel histone deacetylase inhibitor using this approach and chemogenetically validated its target through in vitro evolution. These results highlight the effectiveness of this platform in accelerating antimalarial drug discovery.