Food and Drug Safety Center

Istradefylline, a selective adenosine A2A receptor antagonist, is approved as an adjunct to levodopa in Parkinson's disease, but its long-term effects on clinically meaningful outcomes are unclear. We aimed to compare the association of istradefylline versus catechol-O-methyltransferase (COMT) inhibitors with mortality, treatment escalation, and disease progression in levodopa-treated Parkinson's disease. We conducted a nationwide cohort study emulating a target trial using the DeSC claims database in Japan. Patients aged ≥50 years with levodopa-treated Parkinson's disease between 2014 and 2023 were included. Strategies were initiation of istradefylline versus COMT inhibitors. Primary outcomes were all-cause mortality, levodopa-equivalent daily dose (LEDD) escalation to ≥1100mg, and dementia or psychosis. Secondary outcomes were fractures, cardiovascular events, pneumonia, and depression. Intention-to-treat and per-protocol effects were estimated using Cox models with propensity score-based overlap weighting. We identified 3190 istradefylline and 7986 COMT inhibitor initiators. In intention-to-treat analysis, istradefylline was associated with lower risks of mortality (hazard ratio [HR] 0.91; 95% CI 0.84-0.99) and LEDD escalation (HR 0.83; 95% CI 0.73-0.94). Associations were stronger in per-protocol analysis (mortality: HR 0.84, 95% CI 0.72-0.97; LEDD escalation: HR 0.71, 95% CI 0.59-0.84). Istradefylline was linked to higher fracture risk (intention-to-treat HR 1.13, 95% CI 1.02-1.25; per protocol HR 1.23, 95% CI 1.07-1.41). No differences were observed for dementia, psychosis, or other outcomes. Istradefylline was associated with reduced mortality and treatment escalation but increased fracture risk compared with COMT inhibitors, supporting further evaluation of adenosine A2A antagonists.

In allergen testing of food products, external quality assessment (EQA) programs are essential to ensure high-precision detection and the reliability of results across testing laboratories. However, conventional spiked samples may not sufficiently reflect the nature of processed foods. Therefore, this study examined the applicability of EQA programs using actual food samples that reflect real-world conditions. Twenty-four commercially available food samples were screened using the ELISA method. A coleslaw dressing (CoD) containing 33.1 μg/g of egg-derived protein which is closest to the labeling reference value of 10 μg/g, was selected. The CoD was diluted with egg-free CoD, resulting in a mean concentration of 10.4±0.6 μg/g (RSD 5.3%).Based on this result, approximately 2 kg of an incurred sample (Sample 1) was prepared for a sample in the pilot study for the EQA program, targeting a concentration of 10 μg/g, and its homogeneity and stability were confirmed. A conventional spiked sample (Sample 2) was also prepared with equivalent quality. A pilot study for the EQA program was conducted with 22 institutions. By using two kinds of ELISA kits, the average concentration was 11.9 μg and 9.7 μg for Sample 1 and 8.6 μg/g and 9.3 μg/g for Sample 2. The performance evaluation using robust statistical methods indicated that nearly all measurement results from the institutions fell within the control limits, suggesting that the incurred sample is beneficial as a test material for the EQA program. These results suggest that EQA programs using incurred samples can contribute to improving the reliability of egg allergen testing in food safety management.

<bold>Background and Aim:</bold> The role of airway mucus plugging in asthma pathophysiology is well-established. However, its relationship with infectious episodes and type 2 inflammation remains unclear in refractory asthma with bronchiectasis. As part of the BEXAS study (Nomura N, et al. <italic>Respir Res</italic> 2022; 23: 365), this study aimed to clarify the association between mucus plugging, infectious episodes, and type 2 inflammation, with a specific focus on plug location. <bold>Methods:</bold> Patients with refractory asthma complicated by bronchiectasis, but not with allergic bronchopulmonary aspergillosis, were included, if they had high-resolution CT images suitable for mucus score evaluation. Mucus plugging was scored separately for bilateral upper and lower lobes, as well as for the total lung. Cluster analysis was performed using mucus scores in the upper and lower lobes and the number of lobes affected by bronchiolitis. <bold>Results:</bold> Forty-two patients were included, and three distinct clusters were identified. CL 1 (n = 14) was characterized by lower-lobe-dominant mucus plugs, the highest number of bronchiolitis-affected lobes, frequent detection of Pseudomonas, systemic corticosteroid-requiring exacerbations, and bronchopneumonia. This cluster also exhibited the lowest FeNO and %FEV1. CL 2 (n = 6) showed high mucus scores in both lower and upper lobes, along with the highest FeNO levels. CL 3 (n = 22) had the lowest mucus scores overall. The degree of bronchiectasis was comparable among the three clusters. <bold>Conclusions:</bold> Lower-lobe-dominant mucus plugs may reflect the severest phenotype, characterized by frequent bronchiolitis involvement and infectious episodes. The location of mucus plugs may be clinically important.

Identifying genes involved in anxiety is important to elucidate the mechanisms of anxiety disorders. Hatano high avoidance animals (HAA) and low avoidance animals (LAA) are inbred strains that are selected based on their performance in an active avoidance test. HAA shows a higher level of anxiety-like behavior than LAA. The present study focuses on the hippocampus, which is associated with anxiety-like behavior, and used microarray analysis and RT-qPCR to select genes with differential expression in the hippocampus between HAA and LAA (Experiment 1). The microarray analysis revealed differences in 498 gene expressions between HAA and LAA, of which 21 genes were ligand-receptor related in the nervous system. We selected nine genes based on p value and conducted RT-qPCR, which identified seven genes whose expressions were higher in LAA than in HAA. We focused on the gene, neuromedin U receptor 2 (Nmur2), which showed significantly different expression levels between HAA and LAA. Further, we conducted a behavioral test to evaluate anxiety levels by administering neuromedin U (NmU), an agonist for NmUR2, into the hippocampus (Experiment 2). NmU treatment did not affect the results of the open field test or the elevated plus maze test, which are unconditioned response models of anxiety. However, in the passive avoidance test, a conditioned response model of anxiety, the NmU group showed less anxiety-like behavior than the control group. This is the first study to show that NmU suppresses the conditioned response model of anxiety via the hippocampus, indicating that NmUR2 in the hippocampus may be involved in anxiety-like behavior.

The Epidermal Sensitization Assay (EpiSensA) is a reconstructed human epidermis (RhE)-based gene expression assay for predicting the skin sensitization potential of chemicals. Since the RhE model is covered by a stratified stratum corneum, various kinds of test chemicals, including lipophilic ones and pre-/pro-haptens, can be tested with a route of exposure akin to an in vivo assay and human exposure. This article presents the results of a formally managed validation study of the EpiSensA that was carried out by three participating laboratories. The purpose of this validation study was to assess transferability of the EpiSensA to new laboratories along with its within- (WLR) and between-laboratory reproducibility (BLR). The validation study was organized into two independent stages. As demonstrated during the first stage, where three sensitizers and one non-sensitizer were correctly predicted by all participating laboratories, the EpiSensA was successfully transferred to all three participating laboratories. For Phase I of the second stage, each participating laboratory performed three experiments with an identical set of 15 coded test chemicals resulting in WLR of 93.3%, 93.3%, and 86.7%, respectively. Furthermore, when the results from the 15 test chemicals were combined with those of the additional 12 chemicals tested in Phase II of the second stage, the BLR for 27 test chemicals was 88.9%. Moreover, the predictive capacity among the three laboratories showed 92.6% sensitivity, 63.0% specificity, 82.7% accuracy, and 77.8% balanced accuracy based on murine local lymph node assay (LLNA) results. Overall, this validation study concluded that EpiSensA is easily transferable and sufficiently robust for assessing the skin sensitization potential of chemicals.

Austenitic stainless steel gears were fabricated via the fine blanking process that can be used for mass production. A carbon-supersaturated (CS)-matrix high-speed steel punch was prepared to minimize the adhesive and abrasive wear damage. Its edge profile was tailored and finished to control the local metal flow around the punch edges and edge corners. This CS punch was utilized in fine blanking the AISI304 austenitic stainless steel gears. Ball-on-disc (BOD) testing was first employed to describe the frictional behavior of the CS tool steel disc against the AISI304 stainless steel balls. SEM-EDX analysis on the wear track revealed that a free-carbon tribofilm was formed in situ in the wear track to prevent adhesive wear via galling on the tool steel disc. No significant adhesive or abrasive wear was detected on the punch edges and punch edge corners after continuously fine blanking with 50 strokes. AISI304 gears were produced to have fully burnished surfaces. Their pitches, widths and circles were measured to evaluate their gear-grade balancing during the fine blanking process. The stabilized gear-grade balancing in JIS-9 to JIS-10 grades was attained for these as-blanked AISI304 gears without finishing processes.

The case-crossover study has been proposed as a suitable design when a brief exposure causes a transient change in risk of an acute-onset disease. In pharmacoepidemiology, the condition of "brief exposure" is rarely satisfied because drug use is often chronic or successive, which may result in bias due to within-subject exposure dependency. We describe a simulation of a case-crossover study conducted within a cohort, where patients successively used a drug for 60 or more days and the rate ratio for the outcome occurrence was 4.0. Standard conditional logistic regression for the analysis produced overestimated odds ratios up to 7.8. This bias due to within-subject exposure dependency from chronic use can be removed by the Mantel-Haenszel method, or by our recently proposed weighting method. We also show that when some patients are censored after switching to another drug, a lack of pairwise exchangeability causes bias which is similar to bias due to an exposure time trend. This bias can be removed by the case-time-control design. We show that bias due to within-subject exposure dependency and lack of pairwise exchangeability occur independently and can occur separately or simultaneously, and how to detect and remove them.

We modified a method for determining methanol content in detergents used in kitchens. Furthermore, an inter-laboratory study was conducted in 10 laboratories to validate the modified method. In this study, two concentrations of samples were blindly coded. Each laboratory determined the methanol content in each sample according to a protocol. The determined values were statistically analyzed according to an international harmonized guideline. HorRat values were calculated based on the reproducibility relative standard deviation (RSDR) which was estimated from the interlaboratory study, and predicted RSDR calculated from the Horwitz/Thompson equation. The HorRat values of the two samples were 0.8 and 1.8, meeting the performance criteria of less than 2 set by the Codex Alimentarius for analytical method approval. These results confirm that this modified analytical method shows good performance as an analytical method for determining methanol content in kitchen detergents.

The present study was conducted to survey the influence of canola oil (CAN) ingestion on the steroid hormone production in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP were fed a diet containing 10 wt/wt% soybean oil (SOY, the control) or CAN as the sole dietary fat for 8 weeks. Plasma concentration of luteinizing hormone (LH) was similar in the 2 dietary groups. However, the plasma testosterone level in the CAN group, 1.36 ± 0.271 ng/mL, was lower than in the SOY group, 2.79 ± 0.514 ng/mL (p < 0.05, unpaired t-test; n = 10), and plasma concentration of aldosterone in the CAN group, 345 ± 79.6 pg/mL, was higher than in the SOY group, 159 ± 33.7 pg/mL (p < 0.05, unpaired t-test; n = 10). In the testis, the expressions of mRNA for StAR, CYP11A1, CYP17, 3βHSD and 17βHSD and the amounts of the corresponding proteins were significantly decreased. However, in the adrenal gland, the expressions of mRNA for StAR, CYP11A1, 3βHSD and CYP11B1 in the CAN group were not different from those in the SOY group, but the expression of mRNA and the amount of the corresponding protein for CYP11B2 were increased significantly in the CAN group. These findings are indicative of a peripheral, testicular toxicity of CAN. The decreased testosterone and the concomitantly increased aldosterone may play a role in the aggravation by CAN of the genetic diseases (i.e., metabolic syndrome-like complications) in male SHRSP.

IntroductionHip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records.Methods and analysisThis retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported.Ethics and disseminationEach participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences.